Illuminating Function of the Understudied Druggable Kinome

Gary L. Johnson, Ph.D.
Kenan Distinguished Professor and Chair
Department of Pharmacology
School of Medicine
School of Medicine
University of North Carolina, Chapel Hill

Contacts/Links

Harvard Program in Therapeutic Science:
@shawnmgomez

Overview

Dr. Gary L. Johnson has established a network of collaborators; Dr. Shawn Gomez (UNC), Dr. Ben Major (UNC), Dr. Tim Willson (SGC), Dr. Reid Townsend (WU), and Dr. Peter Sorger (HMS), to tackle the illumination of function of the understudied druggable kinome. Their work includes technologies of Multiplex Inhibitor Beads (MIB) / Mass Spectrometry (MS) to identify kinase activation status in response to perturbants, and applied to model cell lines and Patient Derived xenographs. These information along with collection of other data will be incorporated in the building of a Dark Kinase Knowledgebase (DKK) that provides gene-by-gene and network-level information on the dark kinome and its interaction with other signal transduction and regulatory networks.

NIH grant number:  1U24DK116204-01

Progress on IDG project as tracked by Protein Illumination Timeline:
Kinase Chemical Tools: https://druggablegenome.net/ProteinTimelineKinaseChemicalTools
Kinase Proteomics: https://druggablegenome.net/ProteinTimelineKinaseProteomics

Informatic resources developed by DRGC-Kinase:
Dark Kinome Knowledgebase: https://darkkinome.org/

GITHUB LINK: 134 Kinase https://github.com/sorgerlab/DarkKinome

Additional collaborators:

  • Shawn Gomez, Ph.D.

Associate Professor in Department of Biomedical Engineering
Adjunct Assistant Professor in Department of Computer Science

  • Ben Major, Ph.D.

Associate Professor in Department of Cell Biology & Physiology
Assistant Professor in Department of Computer Science

  • Tim Willson, Ph.D.

Chief Scientist at Structural Genomics Consortium
Research Professor at Eshelman School of Pharmacy
University of North Carolina, Chapel Hill

  • Reid Townsend, M.D., Ph.D.

Professor of Medicine
Director, Mass Spectrometry Resource
Washington University in St. Louis

  • Peter Sorger, Ph.D

Otto Krayer Professor
Systems Pharmacology
Harvard Medical School

DRGC-Kinase Publications:

  1. Gomez SM, Axtman AD, Willson TM, Major MB, Townsend RR, Sorger PK, Johnson GL. Illuminating function of the understudied druggable kinome. Drug Discov Today. 2024 Mar;29(3):103881. doi: 10.1016/j.drudis.2024.103881. Epub 2024 Jan 11. PMID: 38218213.
  2. Asressu KH, Smith JL, Dickmander RJ, Moorman NJ, Wellnitz J, Popov KI, Axtman AD, Willson TM. Synthesis of 5-Benzylamino and 5-Alkylamino-Substituted Pyrimido[4,5-c]quinoline Derivatives as CSNK2A Inhibitors with Antiviral Activity. Pharmaceuticals (Basel). 2024 Feb 27;17(3):306. doi: 10.3390/ph17030306. PMID: 38543092
  3. Galal KA, Krämer A, Strickland BG, Smith JL, Dickmander RJ, Moorman NJ, Willson TM. Identification of 4-(6-((2-methoxyphenyl)amino)pyrazin-2-yl)benzoic acids as CSNK2A inhibitors with antiviral activity and improved selectivity over PIM3. bioRxiv [Preprint]. 2023 Dec 5:2023.12.04.569845. doi: 10.1101/2023.12.04.569845. Update in: Bioorg Med Chem Lett. 2024 Jan 8;99:129617. PMID: 38106118; PMCID: PMC10723276.
  4. Joisa CU, Chen KA, Berginski ME, Golitz BT, Jenner MR, Herrera Loeza G, Yeh JJ, Gomez SM. Integrated single-dose kinome profiling data is predictive of cancer cell line sensitivity to kinase inhibitors. PeerJ. 2023 Nov 16;11:e16342. doi: 10.7717/peerj.16342. PMID: 38025707; PMCID: PMC10657565.
  5. Tiek D, Wells CI, Schröder M, Song X, Alamillo-Ferrer C, Goenka A, Iglesia R, Lu M, Hu B, Kwarcinski F, Sintha P, de Silva C, Hossain MA, Picado A, Zuercher W, Zutshi R, Knapp S, Riggins RB, Cheng SY, Drewry DH. SGC-CLK-1: A chemical probe for the Cdc2-like kinases CLK1, CLK2, and CLK4. Curr Res Chem Biol. 2023;3:100045. doi: 10.1016/j.crchbi.2023.100045. Epub 2023 Sep 22. PMID: 38009092; PMCID: PMC10673624.
  6. Chen H, Lye MF, Gorgulla C, Ficarro SB, Cuny GD, Scott DA, Wu F, Rothlauf PW, Wang X, Fernandez R, Pesola JM, Draga S, Marto JA, Hogle JM, Arthanari H, Coen DM. A small molecule exerts selective antiviral activity by targeting the human cytomegalovirus nuclear egress complex. PLoS Pathog. 2023 Nov 17;19(11):e1011781. doi: 10.1371/journal.ppat.1011781. PMID: 37976321; PMCID: PMC10691697.
  7. Cruite JT, Nowak RP, Donovan KA, Ficarro SB, Huang H, Liu H, Liu Y, Marto JA, Metivier RJ, Fischer ES, Jones LH. Covalent Stapling of the Cereblon Sensor Loop Histidine Using Sulfur-Heterocycle Exchange. ACS Med Chem Lett. 2023 Oct 24;14(11):1576-1581. doi: 10.1021/acsmedchemlett.3c00371. PMID: 37974938; PMCID: PMC10641907.
  8. Nowak RP, Ragosta L, Huerta F, Liu H, Ficarro SB, Cruite JT, Metivier RJ, Donovan KA, Marto JA, Fischer ES, Zerfas BL, Jones LH. Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead. RSC Chem Biol. 2023 Aug 31;4(11):906-912. doi: 10.1039/d3cb00103b. PMID: 37920397; PMCID: PMC10619143.
  9. Yang X, Ong HW, Dickmander RJ, Smith JL, Brown JW, Tao W, Chang E, Moorman NJ, Axtman AD, Willson TM. Optimization of 3-Cyano-7-cyclopropylamino- pyrazolo[1,5-a]pyrimidines toward the Development of an In Vivo Chemical Probe for CSNK2A. ACS Omega. 2023 Oct 10;8(42):39546-39561. doi: 10.1021/acsomega.3c05377. PMID: 37901516; PMCID: PMC10600890.
  10. Wamsley NT, Wilkerson EM, Guan L, LaPak KM, Schrank TP, Holmes BJ, Sprung RW, Gilmore PE, Gerndt SP, Jackson RS, Paniello RC, Pipkorn P, Puram SV, Rich JT, Townsend RR, Zevallos JP, Zolkind P, Le QT, Goldfarb D, Major MB. Targeted Proteomic Quantitation of NRF2 Signaling and Predictive Biomarkers in HNSCC. Mol Cell Proteomics. 2023 Nov;22(11):100647. doi: 10.1016/j.mcpro.2023.100647. Epub 2023 Sep 15. PMID: 37716475; PMCID: PMC10587640.
  11. Anderson B, Rosston P, Ong HW, Hossain MA, Davis-Gilbert ZW, Drewry DH. How many kinases are druggable? A review of our current understanding. Biochem J. 2023 Aug 30;480(16):1331-1363. doi: 10.1042/BCJ20220217. PMID: 37642371; PMCID: PMC10586788.
  12. Fritch EJ, Mordant AL, Gilbert TSK, Wells CI, Yang X, Barker NK, Madden EA, Dinnon KH 3rd, Hou YJ, Tse LV, Castillo IN, Sims AC, Moorman NJ, Lakshmanane P, Willson TM, Herring LE, Graves LM, Baric RS. Investigation of the Host Kinome Response to Coronavirus Infection Reveals PI3K/mTOR Inhibitors as Betacoronavirus Antivirals. J Proteome Res. 2023 Oct 6;22(10):3159-3177. doi: 10.1021/acs.jproteome.3c00182. Epub 2023 Aug 27. PMID: 37634194.
  13. Liu C, Kutchukian P, Nguyen ND, AlQuraishi M, Sorger PK. A Hybrid Structure- Based Machine Learning Approach for Predicting Kinase Inhibition by Small Molecules. J Chem Inf Model. 2023 Sep 11;63(17):5457-5472. doi: 10.1021/acs.jcim.3c00347. Epub 2023 Aug 18. PMID: 37595065; PMCID: PMC10498990.
  14. Joisa CU, Chen KA, Beville S, Stuhlmiller T, Berginski ME, Okumu D, Golitz BT, Johnson GL, Gomez SM. Combined kinome inhibition states are predictive of cancer cell line sensitivity to kinase inhibitor combination therapies. bioRxiv [Preprint]. 2023 Aug 3:2023.08.01.551346. doi: 10.1101/2023.08.01.551346. Update in: Pac Symp Biocomput. 2024;29:276-290. PMID: 37577663; PMCID: PMC10418192.
  15. Castano A, Silvestre M, Wells CI, Sanderson JL, Ferrer CA, Ong HW, Lang Y, Richardson W, Silvaroli JA, Bashore FM, Smith JL, Genereux IM, Dempster K, Drewry DH, Pabla NS, Bullock AN, Benke TA, Ultanir SK, Axtman AD. Discovery and characterization of a specific inhibitor of serine-threonine kinase cyclin- dependent kinase-like 5 (CDKL5) demonstrates role in hippocampal CA1 physiology. Elife. 2023 Jul 25;12:e88206. doi: 10.7554/eLife.88206. PMID: 37490324; PMCID: PMC10406435.
  16. Flint AC, Mitchell DK, Angus SP, Smith AE, Bessler W, Jiang L, Mang H, Li X, Lu Q, Rodriguez B, Sandusky GE, Masters AR, Zhang C, Dang P, Koenig J, Johnson GL, Shen W, Liu J, Aggarwal A, Donoho GP, Willard MD, Bhagwat SV, Clapp DW, Rhodes SD. Combined CDK4/6 and ERK1/2 Inhibition Enhances Antitumor Activity in NF1-Associated Plexiform Neurofibroma. Clin Cancer Res. 2023 Sep 1;29(17):3438-3456. doi: 10.1158/1078-0432.CCR-22-2854. PMID: 37406085.
  17. Yang X, Ong HW, Dickmander RJ, Smith JL, Brown JW, Tao W, Chang E, Moorman NJ, Axtman AD, Willson TM. Optimization of 3-Cyano-7-cyclopropylamino- pyrazolo[1,5-a]pyrimidines Toward the Development of an In Vivo Chemical Probe for CSNK2A. bioRxiv [Preprint]. 2023 Jul 23:2023.05.15.540828. doi: 10.1101/2023.05.15.540828. Update in: ACS Omega. 2023 Oct 10;8(42):39546-39561. PMID: 37292607; PMCID: PMC10245575.
  18. Durcan TM, Axtman AD. Editorial: The next generation of tools and technologies for studying human neurons in a dish. Front Cell Neurosci. 2023 Apr 14;17:1196543. doi: 10.3389/fncel.2023.1196543. PMID: 37124399; PMCID: PMC10140577.
  19. Sahu I, Zhu H, Buhrlage SJ, Marto JA. Proteomic approaches to study ubiquitinomics. Biochim Biophys Acta Gene Regul Mech. 2023 Jun;1866(2):194940. doi: 10.1016/j.bbagrm.2023.194940. Epub 2023 Apr 29. PMID: 37121501; PMCID: PMC10612121.
  20. Ong HW, Liang Y, Richardson W, Lowry ER, Wells CI, Chen X, Silvestre M, Dempster K, Silvaroli JA, Smith JL, Wichterle H, Pabla NS, Ultanir SK, Bullock AN, Drewry DH, Axtman AD. Discovery of a Potent and Selective CDKL5/GSK3 Chemical Probe That Is Neuroprotective. ACS Chem Neurosci. 2023 May 3;14(9):1672-1685. doi: 10.1021/acschemneuro.3c00135. Epub 2023 Apr 21. PMID: 37084253; PMCID: PMC10161233.
  21. Davis-Gilbert ZW, Krämer A, Dunford JE, Howell S, Senbabaoglu F, Wells CI, Bashore FM, Havener TM, Smith JL, Hossain MA, Oppermann U, Drewry DH, Axtman AD. Discovery of a Potent and Selective Naphthyridine-Based Chemical Probe for Casein Kinase 2. ACS Med Chem Lett. 2023 Mar 14;14(4):432-441. doi: 10.1021/acsmedchemlett.2c00530. PMID: 37077385; PMCID: PMC10108397.
  22. Bashore FM, Marquez AB, Chaikuad A, Howell S, Dunn AS, Beltran AA, Smith JL, Drewry DH, Beltran AS, Axtman AD. Modulation of tau tubulin kinases (TTBK1 and TTBK2) impacts ciliogenesis. Sci Rep. 2023 Apr 14;13(1):6118. doi: 10.1038/s41598-023-32854-4. PMID: 37059819; PMCID: PMC10104807.
  23. Yang X, Smith JL, Beck MT, Wilkinson JM, Michaud A, Vasta JD, Robers MB, Willson TM. Development of Cell Permeable NanoBRET Probes for the Measurement of PLK1 Target Engagement in Live Cells. Molecules. 2023 Mar 25;28(7):2950. doi: 10.3390/molecules28072950. PMID: 37049713; PMCID: PMC10095950.
  24. Berginski ME, Joisa CU, Golitz BT, Gomez SM. Kinome inhibition states and multiomics data enable prediction of cell viability in diverse cancer types. PLoS Comput Biol. 2023 Feb 21;19(2):e1010888. doi: 10.1371/journal.pcbi.1010888. PMID: 36809237; PMCID: PMC9983880.
  25. Ong HW, Liang Y, Richardson W, Lowry ER, Wells CI, Chen X, Silvestre M, Dempster K, Silvaroli JA, Smith JL, Wichterle H, Pabla NS, Ultanir SK, Bullock AN, Drewry DH, Axtman AD. A Potent and Selective CDKL5/GSK3 Chemical Probe is Neuroprotective. bioRxiv [Preprint]. 2023 Feb 10:2023.02.09.527935. doi: 10.1101/2023.02.09.527935. Update in: ACS Chem Neurosci. 2023 Apr 21;: PMID: 36798313; PMCID: PMC9934649.
  26. Chan WC, Liu X, Magin RS, Girardi NM, Ficarro SB, Hu W, Tarazona Guzman MI, Starnbach CA, Felix A, Adelmant G, Varca AC, Hu B, Bratt AS, DaSilva E, Schauer NJ, Jaen Maisonet I, Dolen EK, Ayala AX, Marto JA, Buhrlage SJ. Accelerating inhibitor discovery for deubiquitinating enzymes. Nat Commun. 2023 Feb 8;14(1):686. doi: 10.1038/s41467-023-36246-0. PMID: 36754960; PMCID: PMC9908924.
  27. Wells C, Liang Y, Pulliam TL, Lin C, Awad D, Eduful B, O'Byrne S, Hossain MA, Catta-Preta CMC, Ramos PZ, Gileadi O, Gileadi C, Couñago RM, Stork B, Langendorf CG, Nay K, Oakhill JS, Mukherjee D, Racioppi L, Means AR, York B, McDonnell DP, Scott JW, Frigo DE, Drewry DH. SGC-CAMKK2-1: A Chemical Probe for CAMKK2. Cells. 2023 Jan 11;12(2):287. doi: 10.3390/cells12020287. PMID: 36672221; PMCID: PMC9856672.
  28. Johnson JL, Yaron TM, Huntsman EM, Kerelsky A, Song J, Regev A, Lin TY, Liberatore K, Cizin DM, Cohen BM, Vasan N, Ma Y, Krismer K, Robles JT, van de Kooij B, van Vlimmeren AE, Andrée-Busch N, Käufer NF, Dorovkov MV, Ryazanov AG, Takagi Y, Kastenhuber ER, Goncalves MD, Hopkins BD, Elemento O, Taatjes DJ, Maucuer A, Yamashita A, Degterev A, Uduman M, Lu J, Landry SD, Zhang B, Cossentino I, Linding R, Blenis J, Hornbeck PV, Turk BE, Yaffe MB, Cantley LC. An atlas of substrate specificities for the human serine/threonine kinome. Nature. 2023 Jan;613(7945):759-766. doi: 10.1038/s41586-022-05575-3. Epub 2023 Jan 11. PMID: 36631611; PMCID: PMC9876800.
  29. Mills CE, Subramanian K, Hafner M, Niepel M, Gerosa L, Chung M, Victor C, Gaudio B, Yapp C, Nirmal AJ, Clark N, Sorger PK. Multiplexed and reproducible high content screening of live and fixed cells using Dye Drop. Nat Commun. 2022 Nov 14;13(1):6918. doi: 10.1038/s41467-022-34536-7. PMID: 36376301; PMCID: PMC9663587.
  30. Drewry DH, Potjewyd FM, Bayati A, Smith JL, Dickmander RJ, Howell S, Taft- Benz S, Min SM, Hossain MA, Heise M, McPherson PS, Moorman NJ, Axtman AD. Identification and Utilization of a Chemical Probe to Interrogate the Roles of PIKfyve in the Lifecycle of β-Coronaviruses. J Med Chem. 2022 Oct 13;65(19):12860-12882. doi: 10.1021/acs.jmedchem.2c00697. Epub 2022 Sep 16. PMID: 36111834; PMCID: PMC9574855.
  31. Mishra S, Kinoshita C, Axtman AD, Young JE. Evaluation of a Selective Chemical Probe Validates That CK2 Mediates Neuroinflammation in a Human Induced Pluripotent Stem Cell-Derived Microglial Model. Front Mol Neurosci. 2022 Jun 14;15:824956. doi: 10.3389/fnmol.2022.824956. Erratum in: Front Mol Neurosci. 2023 Nov 21;16:1334040. PMID: 35774866; PMCID: PMC9239073.
  32. Karim M, Saul S, Ghita L, Sahoo MK, Ye C, Bhalla N, Lo CW, Jin J, Park JG, Martinez-Gualda B, East MP, Johnson GL, Pinsky BA, Martinez-Sobrido L, Asquith CRM, Narayanan A, De Jonghe S, Einav S. Numb-associated kinases are required for SARS-CoV-2 infection and are cellular targets for antiviral strategies. Antiviral Res. 2022 Aug;204:105367. doi: 10.1016/j.antiviral.2022.105367. Epub 2022 Jun 20. PMID: 35738348; PMCID: PMC9212491.
  33. Tiek DM, Erdogdu B, Razaghi R, Jin L, Sadowski N, Alamillo-Ferrer C, Hogg JR, Haddad BR, Drewry DH, Wells CI, Pickett JE, Song X, Goenka A, Hu B, Goldlust SA, Zuercher WJ, Pertea M, Timp W, Cheng SY, Riggins RB. Temozolomide-induced guanine mutations create exploitable vulnerabilities of guanine-rich DNA and RNA regions in drug-resistant gliomas. Sci Adv. 2022 Jun 24;8(25):eabn3471. doi: 10.1126/sciadv.abn3471. Epub 2022 Jun 22. PMID: 35731869; PMCID: PMC9216507.
  34. Zhu H, Mellors JS, Chan WC, Thompson JW, Ficarro SB, Tavares I, Bratt AS, Decker J, Krause M, Kruppa G, Buhrlage SJ, Marto JA. On-Chip Preconcentration Microchip Capillary Electrophoresis Based CE-PRM-LIVE for High-Throughput Selectivity Profiling of Deubiquitinase Inhibitors. Anal Chem. 2022 Jul 12;94(27):9508-9513. doi: 10.1021/acs.analchem.2c01337. Epub 2022 Jun 21. PMID: 35729701; PMCID: PMC10654755.
  35. Yang X, Dickmander RJ, Bayati A, Taft-Benz SA, Smith JL, Wells CI, Madden EA, Brown JW, Lenarcic EM, Yount BL Jr, Chang E, Axtman AD, Baric RS, Heise MT, McPherson PS, Moorman NJ, Willson TM. Host Kinase CSNK2 is a Target for Inhibition of Pathogenic SARS-like β-Coronaviruses. ACS Chem Biol. 2022 Jul 15;17(7):1937-1950. doi: 10.1021/acschembio.2c00378. Epub 2022 Jun 19. PMID: 35723434; PMCID: PMC9236220.
  36. Ficarro SB, Max Alexander W, Tavares I, Marto JA. Open source fraction collector/MALDI spotter for proteomics. HardwareX. 2022 Apr 18;11:e00305. doi: 10.1016/j.ohx.2022.e00305. PMID: 35518277; PMCID: PMC9062586.
  37. Agajanian MJ, Potjewyd FM, Bowman BM, Solomon S, LaPak KM, Bhatt DP, Smith JL, Goldfarb D, Axtman AD, Major MB. Protein proximity networks and functional evaluation of the casein kinase 1 gamma family reveal unique roles for CK1γ3 in WNT signaling. J Biol Chem. 2022 Jun;298(6):101986. doi: 10.1016/j.jbc.2022.101986. Epub 2022 Apr 27. PMID: 35487243; PMCID: PMC9157009.
  38. Asquith CRM, Temme L, East MP, Laitinen T, Pickett J, Kwarcinski FE, Sinha P, Wells CI, Johnson GL, Zutshi R, Drewry DH. Identification of 4-Anilinoquin(az)oline as a Cell-Active Protein Kinase Novel 3 (PKN3) Inhibitor Chemotype. ChemMedChem. 2022 Jun 20;17(12):e202200161. doi: 10.1002/cmdc.202200161. Epub 2022 May 9. PMID: 35403825; PMCID: PMC9233141.
  39. Kirchoff KE, Gomez SM. EMBER: multi-label prediction of kinase-substrate phosphorylation events through deep learning. Bioinformatics. 2022 Apr 12;38(8):2119-2126. doi: 10.1093/bioinformatics/btac083. PMID: 35157015; PMCID: PMC9004653.
  40. Yang X, Dickmander RJ, Bayati A, Taft-Benz SA, Smith JL, Wells CI, Madden EA, Brown JW, Lenarcic EM, Yount BL Jr, Chang E, Axtman AD, Baric RS, Heise MT, McPherson PS, Moorman NJ, Willson TM. Host kinase CSNK2 is a target for inhibition of pathogenic β-coronaviruses including SARS-CoV-2. bioRxiv [Preprint]. 2022 Jan 26:2022.01.03.474779. doi: 10.1101/2022.01.03.474779. Update in: ACS Chem Biol. 2022 Jun 19;: PMID: 35018375; PMCID: PMC8750650.
  41. East MP, Johnson GL. Adaptive chromatin remodeling and transcriptional changes of the functional kinome in tumor cells in response to targeted kinase inhibition. J Biol Chem. 2022 Feb;298(2):101525. doi: 10.1016/j.jbc.2021.101525. Epub 2021 Dec 24. PMID: 34958800; PMCID: PMC8888345.
  42. Zhu H, Ficarro SB, Alexander WM, Fleming LE, Adelmant G, Zhang T, Willetts M, Decker J, Brehmer S, Krause M, East MP, Gray NS, Johnson GL, Kruppa G, Marto JA. PRM-LIVE with Trapped Ion Mobility Spectrometry and Its Application in Selectivity Profiling of Kinase Inhibitors. Anal Chem. 2021 Oct 19;93(41):13791-13799. doi: 10.1021/acs.analchem.1c02349. Epub 2021 Oct 4. PMID: 34606255; PMCID: PMC9297317.
  43. Axtman AD. Characterizing the role of the dark kinome in neurodegenerative disease - A mini review. Biochim Biophys Acta Gen Subj. 2021 Dec;1865(12):130014. doi: 10.1016/j.bbagen.2021.130014. Epub 2021 Sep 20. PMID: 34547390.
  44. Schirmer AU, Driver LM, Zhao MT, Wells CI, Pickett JE, O'Bryne SN, Eduful BJ, Yang X, Howard L, You S, Devi GR, DiGiovanni J, Freedland SJ, Chi JT, Drewry DH, Macias E. Non-canonical role of Hippo tumor suppressor serine/threonine kinase 3 STK3 in prostate cancer. Mol Ther. 2022 Jan 5;30(1):485-500. doi: 10.1016/j.ymthe.2021.08.029. Epub 2021 Aug 25. PMID: 34450249; PMCID: PMC8753456.
  45. Drewry DH, Annor-Gyamfi JK, Wells CI, Pickett JE, Dederer V, Preuss F, Mathea S, Axtman AD. Identification of Pyrimidine-Based Lead Compounds for Understudied Kinases Implicated in Driving Neurodegeneration. J Med Chem. 2022 Jan 27;65(2):1313-1328. doi: 10.1021/acs.jmedchem.1c00440. Epub 2021 Aug 1. PMID: 34333981; PMCID: PMC8802302.
  46. Eduful BJ, O'Byrne SN, Temme L, Asquith CRM, Liang Y, Picado A, Pilotte JR, Hossain MA, Wells CI, Zuercher WJ, Catta-Preta CMC, Zonzini Ramos P, Santiago AS, Couñago RM, Langendorf CG, Nay K, Oakhill JS, Pulliam TL, Lin C, Awad D, Willson TM, Frigo DE, Scott JW, Drewry DH. Hinge Binder Scaffold Hopping Identifies Potent Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 (CAMKK2) Inhibitor Chemotypes. J Med Chem. 2021 Aug 12;64(15):10849-10877. doi: 10.1021/acs.jmedchem.0c02274. Epub 2021 Jul 15. PMID: 34264658; PMCID: PMC8365604.
  47. Cichońska A, Ravikumar B, Allaway RJ, Wan F, Park S, Isayev O, Li S, Mason M, Lamb A, Tanoli Z, Jeon M, Kim S, Popova M, Capuzzi S, Zeng J, Dang K, Koytiger G, Kang J, Wells CI, Willson TM; IDG-DREAM Drug-Kinase Binding Prediction Challenge Consortium; Oprea TI, Schlessinger A, Drewry DH, Stolovitzky G, Wennerberg K, Guinney J, Aittokallio T. Crowdsourced mapping of unexplored target space of kinase inhibitors. Nat Commun. 2021 Jun 3;12(1):3307. doi: 10.1038/s41467-021-23165-1. PMID: 34083538; PMCID: PMC8175708.
  48. Wang CB, Lorente-Macías Á, Wells C, Pickett JE, Picado A, Zuercher WJ, Axtman AD. Towards a RIOK2 chemical probe: cellular potency improvement of a selective 2-(acylamino)pyridine series. RSC Med Chem. 2020 Nov 11;12(1):129-136. doi: 10.1039/d0md00292e. PMID: 34046605; PMCID: PMC8130602.
  49. Jiang B, Gao Y, Che J, Lu W, Kaltheuner IH, Dries R, Kalocsay M, Berberich MJ, Jiang J, You I, Kwiatkowski N, Riching KM, Daniels DL, Sorger PK, Geyer M, Zhang T, Gray NS. Discovery and resistance mechanism of a selective CDK12 degrader. Nat Chem Biol. 2021 Jun;17(6):675-683. doi: 10.1038/s41589-021-00765-y. Epub 2021 Mar 22. PMID: 33753926; PMCID: PMC8590456.
  50. Rodriguez S, Hug C, Todorov P, Moret N, Boswell SA, Evans K, Zhou G, Johnson NT, Hyman BT, Sorger PK, Albers MW, Sokolov A. Machine learning identifies candidates for drug repurposing in Alzheimer's disease. Nat Commun. 2021 Feb 15;12(1):1033. doi: 10.1038/s41467-021-21330-0. PMID: 33589615; PMCID: PMC7884393.
  51. Wells CI, Drewry DH, Pickett JE, Tjaden A, Krämer A, Müller S, Gyenis L, Menyhart D, Litchfield DW, Knapp S, Axtman AD. Development of a potent and selective chemical probe for the pleiotropic kinase CK2. Cell Chem Biol. 2021 Apr 15;28(4):546-558.e10. doi: 10.1016/j.chembiol.2020.12.013. Epub 2021 Jan 22. PMID: 33484635; PMCID: PMC8864761.
  52. Wells CI, Al-Ali H, Andrews DM, Asquith CRM, Axtman AD, Dikic I, Ebner D, Ettmayer P, Fischer C, Frederiksen M, Futrell RE, Gray NS, Hatch SB, Knapp S, Lücking U, Michaelides M, Mills CE, Müller S, Owen D, Picado A, Saikatendu KS, Schröder M, Stolz A, Tellechea M, Turunen BJ, Vilar S, Wang J, Zuercher WJ, Willson TM, Drewry DH. The Kinase Chemogenomic Set (KCGS): An Open Science Resource for Kinase Vulnerability Identification. Int J Mol Sci. 2021 Jan 8;22(2):566. doi: 10.3390/ijms22020566. PMID: 33429995; PMCID: PMC7826789.
  53. Donovan KA, Ferguson FM, Bushman JW, Eleuteri NA, Bhunia D, Ryu S, Tan L, Shi K, Yue H, Liu X, Dobrovolsky D, Jiang B, Wang J, Hao M, You I, Teng M, Liang Y, Hatcher J, Li Z, Manz TD, Groendyke B, Hu W, Nam Y, Sengupta S, Cho H, Shin I, Agius MP, Ghobrial IM, Ma MW, Che J, Buhrlage SJ, Sim T, Gray NS, Fischer ES. Mapping the Degradable Kinome Provides a Resource for Expedited Degrader Development. Cell. 2020 Dec 10;183(6):1714-1731.e10. doi: 10.1016/j.cell.2020.10.038. Epub 2020 Dec 3. PMID: 33275901; PMCID: PMC10294644.
  54. Picado A, Chaikuad A, Wells CI, Shrestha S, Zuercher WJ, Pickett JE, Kwarcinski FE, Sinha P, de Silva CS, Zutshi R, Liu S, Kannan N, Knapp S, Drewry DH, Willson TM. A Chemical Probe for Dark Kinase STK17B Derives Its Potency and High Selectivity through a Unique P-Loop Conformation. J Med Chem. 2020 Dec 10;63(23):14626-14646. doi: 10.1021/acs.jmedchem.0c01174. Epub 2020 Nov 20. PMID: 33215924; PMCID: PMC7816213.
  55. Berginski ME, Moret N, Liu C, Goldfarb D, Sorger PK, Gomez SM. The Dark Kinase Knowledgebase: an online compendium of knowledge and experimental results of understudied kinases. Nucleic Acids Res. 2021 Jan 8;49(D1):D529-D535. doi: 10.1093/nar/gkaa853. PMID: 33079988; PMCID: PMC7778917.
  56. O'Byrne SN, Eduful BJ, Willson TM, Drewry DH. Concise, gram-scale synthesis of furo[2,3-b]pyridines with functional handles for chemoselective cross- coupling. Tetrahedron Lett. 2020 Sep 17;61(38):152353. doi: 10.1016/j.tetlet.2020.152353. Epub 2020 Aug 16. PMID: 33012852; PMCID: PMC7526865.
  57. Tamir TY, Drewry DH, Wells C, Major MB, Axtman AD. PKIS deep dive yields a chemical starting point for dark kinases and a cell active BRSK2 inhibitor. Sci Rep. 2020 Sep 28;10(1):15826. doi: 10.1038/s41598-020-72869-9. PMID: 32985588; PMCID: PMC7522982.
  58. Ducker M, Millar V, Ebner D, Szele FG. A Semi-automated and Scalable 3D Spheroid Assay to Study Neuroblast Migration. Stem Cell Reports. 2020 Sep 8;15(3):789-802. doi: 10.1016/j.stemcr.2020.07.012. Epub 2020 Aug 6. PMID: 32763162; PMCID: PMC7486343.
  59. Liu Y, Ferguson FM, Li L, Kuljanin M, Mills CE, Subramanian K, Harshbarger W, Gondi S, Wang J, Sorger PK, Mancias JD, Gray NS, Westover KD. Chemical Biology Toolkit for DCLK1 Reveals Connection to RNA Processing. Cell Chem Biol. 2020 Oct 15;27(10):1229-1240.e4. doi: 10.1016/j.chembiol.2020.07.011. Epub 2020 Aug 4. PMID: 32755567; PMCID: PMC8053042.
  60. Goulet DR, Foster JP 2nd, Zawistowski JS, Bevill SM, Noël MP, Olivares- Quintero JF, Sciaky N, Singh D, Santos C, Pattenden SG, Davis IJ, Johnson GL. Discrete Adaptive Responses to MEK Inhibitor in Subpopulations of Triple- Negative Breast Cancer. Mol Cancer Res. 2020 Nov;18(11):1685-1698. doi: 10.1158/1541-7786.MCR-19-1011. Epub 2020 Aug 4. PMID: 32753473; PMCID: PMC7642176.
  61. Tamir TY, Bowman BM, Agajanian MJ, Goldfarb D, Schrank TP, Stohrer T, Hale AE, Siesser PF, Weir SJ, Murphy RM, LaPak KM, Weissman BE, Moorman NJ, Major MB. Gain-of-function genetic screen of the kinome reveals BRSK2 as an inhibitor of the NRF2 transcription factor. J Cell Sci. 2020 Jul 15;133(14):jcs241356. doi: 10.1242/jcs.241356. PMID: 32546533; PMCID: PMC7375482.
  62. Wells CI, Vasta JD, Corona CR, Wilkinson J, Zimprich CA, Ingold MR, Pickett JE, Drewry DH, Pugh KM, Schwinn MK, Hwang BB, Zegzouti H, Huber KVM, Cong M, Meisenheimer PL, Willson TM, Robers MB. Quantifying CDK inhibitor selectivity in live cells. Nat Commun. 2020 Jun 2;11(1):2743. doi: 10.1038/s41467-020-16559-0. PMID: 32488087; PMCID: PMC7265341.
  63. Krahn AI, Wells C, Drewry DH, Beitel LK, Durcan TM, Axtman AD. Defining the Neural Kinome: Strategies and Opportunities for Small Molecule Drug Discovery to Target Neurodegenerative Diseases. ACS Chem Neurosci. 2020 Jul 1;11(13):1871-1886. doi: 10.1021/acschemneuro.0c00176. Epub 2020 Jun 11. PMID: 32464049.
  64. O'Byrne SN, Scott JW, Pilotte JR, Santiago ADS, Langendorf CG, Oakhill JS, Eduful BJ, Couñago RM, Wells CI, Zuercher WJ, Willson TM, Drewry DH. In Depth Analysis of Kinase Cross Screening Data to Identify CAMKK2 Inhibitory Scaffolds. Molecules. 2020 Jan 13;25(2):325. doi: 10.3390/molecules25020325. PMID: 31941153; PMCID: PMC7024175.
  65. Asquith CRM, Murray NH, Pagliarini DJ. ADCK3/COQ8A: the choice target of the UbiB protein kinase-like family. Nat Rev Drug Discov. 2019 Oct;18(11):815. doi: 10.1038/d41573-019-00158-w. PMID: 31673128; PMCID: PMC7062282.
  66. Singhal S, Gomez SM, Burch CL. Recombination drives the evolution of mutational robustness. Curr Opin Syst Biol. 2019 Feb;13:142-149. doi: 10.1016/j.coisb.2018.12.003. Epub 2019 Jan 2. PMID: 31572829; PMCID: PMC6768415.
  67. Wong JP, Stuhlmiller TJ, Giffin LC, Lin C, Bigi R, Zhao J, Zhang W, Bravo Cruz AG, Park SI, Earp HS, Dittmer DP, Frye SV, Wang X, Johnson GL, Damania B. Kinome profiling of non-Hodgkin lymphoma identifies Tyro3 as a therapeutic target in primary effusion lymphoma. Proc Natl Acad Sci U S A. 2019 Aug 13;116(33):16541-16550. doi: 10.1073/pnas.1903991116. Epub 2019 Jul 25. PMID: 31346082; PMCID: PMC6697815.
  68. Axtman A, Drewry D, Wells C. CDK16: the pick of the understudied PCTAIRE kinases. Nat Rev Drug Discov. 2019 Jul;18(7):489. doi: 10.1038/d41573-019-00076-x. PMID: 31267068.
  69. Drewry DH, Wells CI, Zuercher WJ, Willson TM. A Perspective on Extreme Open Science: Companies Sharing Compounds without Restriction. SLAS Discov. 2019 Jun;24(5):505-514. doi: 10.1177/2472555219838210. Epub 2019 Apr 29. PMID: 31034310; PMCID: PMC6624833.
  70. Bevill SM, Olivares-Quintero JF, Sciaky N, Golitz BT, Singh D, Beltran AS, Rashid NU, Stuhlmiller TJ, Hale A, Moorman NJ, Santos CM, Angus SP, Zawistowski JS, Johnson GL. GSK2801, a BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer. Mol Cancer Res. 2019 Jul;17(7):1503-1518. doi: 10.1158/1541-7786.MCR-18-1121. Epub 2019 Apr 18. PMID: 31000582; PMCID: PMC6610760.
  71. Moret N, Clark NA, Hafner M, Wang Y, Lounkine E, Medvedovic M, Wang J, Gray N, Jenkins J, Sorger PK. Cheminformatics Tools for Analyzing and Designing Optimized Small-Molecule Collections and Libraries. Cell Chem Biol. 2019 May 16;26(5):765-777.e3. doi: 10.1016/j.chembiol.2019.02.018. Epub 2019 Apr 4. PMID: 30956147; PMCID: PMC6526536.
  72. Ferguson FM, Doctor ZM, Ficarro SB, Browne CM, Marto JA, Johnson JL, Yaron TM, Cantley LC, Kim ND, Sim T, Berberich MJ, Kalocsay M, Sorger PK, Gray NS. Discovery of Covalent CDK14 Inhibitors with Pan-TAIRE Family Specificity. Cell Chem Biol. 2019 Jun 20;26(6):804-817.e12. doi: 10.1016/j.chembiol.2019.02.015. Epub 2019 Mar 28. PMID: 30930164; PMCID: PMC6588450.
  73. Asquith CRM, Berger BT, Wan J, Bennett JM, Capuzzi SJ, Crona DJ, Drewry DH, East MP, Elkins JM, Fedorov O, Godoi PH, Hunter DM, Knapp S, Müller S, Torrice CD, Wells CI, Earp HS, Willson TM, Zuercher WJ. SGC-GAK-1: A Chemical Probe for Cyclin G Associated Kinase (GAK). J Med Chem. 2019 Mar 14;62(5):2830-2836. doi: 10.1021/acs.jmedchem.8b01213. Epub 2019 Feb 26. PMID: 30768268; PMCID: PMC6567991.
  74. Agajanian MJ, Walker MP, Axtman AD, Ruela-de-Sousa RR, Serafin DS, Rabinowitz AD, Graham DM, Ryan MB, Tamir T, Nakamichi Y, Gammons MV, Bennett JM, Couñago RM, Drewry DH, Elkins JM, Gileadi C, Gileadi O, Godoi PH, Kapadia N, Müller S, Santiago AS, Sorrell FJ, Wells CI, Fedorov O, Willson TM, Zuercher WJ, Major MB. WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop. Cell Rep. 2019 Jan 2;26(1):79-93.e8. doi: 10.1016/j.celrep.2018.12.023. PMID: 30605688; PMCID: PMC6315376.
  75. Foulkes DM, Byrne DP, Yeung W, Shrestha S, Bailey FP, Ferries S, Eyers CE, Keeshan K, Wells C, Drewry DH, Zuercher WJ, Kannan N, Eyers PA. Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells. Sci Signal. 2018 Sep 25;11(549):eaat7951. doi: 10.1126/scisignal.aat7951. PMID: 30254057; PMCID: PMC6553640.
  76. Metz KS, Deoudes EM, Berginski ME, Jimenez-Ruiz I, Aksoy BA, Hammerbacher J, Gomez SM, Phanstiel DH. Coral: Clear and Customizable Visualization of Human Kinome Data. Cell Syst. 2018 Sep 26;7(3):347-350.e1. doi: 10.1016/j.cels.2018.07.001. Epub 2018 Aug 29. PMID: 30172842; PMCID: PMC6366324.
  77. Krulikas LJ, McDonald IM, Lee B, Okumu DO, East MP, Gilbert TSK, Herring LE, Golitz BT, Wells CI, Axtman AD, Zuercher WJ, Willson TM, Kireev D, Yeh JJ, Johnson GL, Baines AT, Graves LM. Application of Integrated Drug Screening/Kinome Analysis to Identify Inhibitors of Gemcitabine-Resistant Pancreatic Cancer Cell Growth. SLAS Discov. 2018 Sep;23(8):850-861. doi: 10.1177/2472555218773045. Epub 2018 May 9. PMID: 29742358; PMCID: PMC6102050.
  78. Collins KAL, Stuhlmiller TJ, Zawistowski JS, East MP, Pham TT, Hall CR, Goulet DR, Bevill SM, Angus SP, Velarde SH, Sciaky N, Oprea TI, Graves LM, Johnson GL, Gomez SM. Proteomic analysis defines kinase taxonomies specific for subtypes of breast cancer. Oncotarget. 2018 Jan 29;9(21):15480-15497. doi: 10.18632/oncotarget.24337. PMID: 29643987; PMCID: PMC5884642.
  79. Oprea TI, Bologa CG, Brunak S, Campbell A, Gan GN, Gaulton A, Gomez SM, Guha R, Hersey A, Holmes J, Jadhav A, Jensen LJ, Johnson GL, Karlson A, Leach AR, Ma'ayan A, Malovannaya A, Mani S, Mathias SL, McManus MT, Meehan TF, von Mering C, Muthas D, Nguyen DT, Overington JP, Papadatos G, Qin J, Reich C, Roth BL, Schürer SC, Simeonov A, Sklar LA, Southall N, Tomita S, Tudose I, Ursu O, Vidovic D, Waller A, Westergaard D, Yang JJ, Zahoránszky-Köhalmi G. Unexplored therapeutic opportunities in the human genome. Nat Rev Drug Discov. 2018 May;17(5):317-332. doi: 10.1038/nrd.2018.14. Epub 2018 Mar 23. Erratum in: Nat Rev Drug Discov. 2018 Mar 23;: PMID: 29472638; PMCID: PMC6339563.
  80. Mundt F, Rajput S, Li S, Ruggles KV, Mooradian AD, Mertins P, Gillette MA, Krug K, Guo Z, Hoog J, Erdmann-Gilmore P, Primeau T, Huang S, Edwards DP, Wang X, Wang X, Kawaler E, Mani DR, Clauser KR, Gao F, Luo J, Davies SR, Johnson GL, Huang KL, Yoon CJ, Ding L, Fenyö D, Ellis MJ, Townsend RR, Held JM, Carr SA, Ma CX. Mass Spectrometry-Based Proteomics Reveals Potential Roles of NEK9 and MAP2K4 in Resistance to PI3K Inhibition in Triple-Negative Breast Cancers. Cancer Res. 2018 May 15;78(10):2732-2746. doi: 10.1158/0008-5472.CAN-17-1990. Epub 2018 Feb 22. PMID: 29472518; PMCID: PMC5955814.
  81. Vasta JD, Corona CR, Wilkinson J, Zimprich CA, Hartnett JR, Ingold MR, Zimmerman K, Machleidt T, Kirkland TA, Huwiler KG, Ohana RF, Slater M, Otto P, Cong M, Wells CI, Berger BT, Hanke T, Glas C, Ding K, Drewry DH, Huber KVM, Willson TM, Knapp S, Müller S, Meisenheimer PL, Fan F, Wood KV, Robers MB. Quantitative, Wide-Spectrum Kinase Profiling in Live Cells for Assessing the Effect of Cellular ATP on Target Engagement. Cell Chem Biol. 2018 Feb 15;25(2):206-214.e11. doi: 10.1016/j.chembiol.2017.10.010. Epub 2017 Nov 22. PMID: 29174542; PMCID: PMC5814754.
  82. Cousins EM, Goldfarb D, Yan F, Roques J, Darr D, Johnson GL, Major MB. Competitive Kinase Enrichment Proteomics Reveals that Abemaciclib Inhibits GSK3β and Activates WNT Signaling. Mol Cancer Res. 2018 Feb;16(2):333-344. doi: 10.1158/1541-7786.MCR-17-0468. Epub 2017 Nov 13. PMID: 29133594; PMCID: PMC5805620.
  83. Asquith CRM, Laitinen T, Bennett JM, Godoi PH, East MP, Tizzard GJ, Graves LM, Johnson GL, Dornsife RE, Wells CI, Elkins JM, Willson TM, Zuercher WJ. Identification and Optimization of 4-Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase. ChemMedChem. 2018 Jan 8;13(1):48-66. doi: 10.1002/cmdc.201700663. Epub 2017 Nov 27. PMID: 29072804; PMCID: PMC5914168.
  84. Drewry DH, Wells CI, Andrews DM, Angell R, Al-Ali H, Axtman AD, Capuzzi SJ, Elkins JM, Ettmayer P, Frederiksen M, Gileadi O, Gray N, Hooper A, Knapp S, Laufer S, Luecking U, Michaelides M, Müller S, Muratov E, Denny RA, Saikatendu KS, Treiber DK, Zuercher WJ, Willson TM. Progress towards a public chemogenomic set for protein kinases and a call for contributions. PLoS One. 2017 Aug 2;12(8):e0181585. doi: 10.1371/journal.pone.0181585. PMID: 28767711; PMCID: PMC5540273.

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