Illuminating Function of the Understudied Druggable Kinome

Contacts/Links

• Shawn Gomez’s Lab: https://gomezlab.org
• Ben Major’s Lab: https://www.med.unc.edu/cellbiophysio/major/
• Tim Willson:  http://www.chemicalprobes.org/tim-willson
• SGC: https://www.thesgc.org/
• Reid Townsend: https://siteman.wustl.edu/research/shared-resources-cores/proteomics-shared-resource/
• Peter Sorger: https://sorger.med.harvard.edu/

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. GSK2801, A BAZ2/BRD9 Bromodomain Inhibitor, Synergizes with BET Inhibitors to Induce Apoptosis in Triple-Negative Breast Cancer.
   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. Mol Cancer Res. 2019 Apr 18. doi: 10.1158/1541-7786.MCR-18-1121. [Epub ahead of print] PMID: 31000582

2. Cheminformatics Tools for Analyzing and Designing Optimized Small-Molecule Collections and Libraries.
   Moret N, Clark NA, Hafner M, Wang Y, Lounkine E, Medvedovic M, Wang J, Gray N, Jenkins J, Sorger PK., 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

3. WNT Activates the AAK1 Kinase to Promote Clathrin-Mediated Endocytosis of LRP6 and Establish a Negative Feedback Loop.
   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., Cell Rep. 2019 Jan 2;26(1):79-93.e8. doi: 10.1016/j.celrep.2018.12.023., PMID: 30605688, PMCID: PMC6315376

4. Proteomic analysis defines kinase taxonomies specific for subtypes of breast cancer.
   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., Oncotarget. 2018 Jan 29;9(21):15480-15497. doi: 10.18632/oncotarget.24337. eCollection 2018 Mar 20.. PMID: 29643987, PMCID: PMC5884642

5. Unexplored therapeutic opportunities in the human genome.
   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., Nat Rev Drug Discov. 2018 May;17(5):317-332. doi: 10.1038/nrd.2018.14. Epub 2018 Mar 23. Review. Erratum in: Nat Rev Drug Discov. 2018 Mar 23. PMID: 29472638, PMCID: PMC6339563

6. Identification and Optimization of 4-Anilinoquinolines as Inhibitors of Cyclin G Associated Kinase.
   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., ChemMedChem. 2018 Jan 8;13(1):48-66. doi: 10.1002/cmdc.201700663. Epub 2017 Nov 27., PMID: 29072804, PMCID: PMC5914168