Chemical proteomics Large-scale DNA sequencing efforts along with systematic functional genomic studies continue to uncover new dependencies of various human diseases. In many cases, these protein 'drivers' have binding pockets or other structural elements which can be leveraged for drug development. However, it remains difficult to efficiently assess the on-/off-target activity of small molecule probes throughout the proteome, hindering the pace of drug discovery. As a result, a significant fraction of the 'druggable genome' remains unexplored. We have developed mass spectrometry-based techniques to characterize the activity of small molecule probes and clinical drugs. These chemoproteomic data establish robust, proteome-wide selectivity and dose-response profiles of small molecule inhibitors. We also use these tools to drive discovery and annotation of new drug targets. In parallel we are creating new reporter probes for use in high-throughput assays designed to measure the stoichiometry of ligand-target engagement in vivo. See papers below and our resources page for more information.
Publications related to chemical proteomics 18. Browne CM, Jiang B, Ficarro SB, Doctor ZM, Johnson JL, Card JD, Sivakumaren SC, Alexander WM, Yaron TM, Murphy CJ, Kwiatkowski NP, Zhang T, Cantley LC, Gray NS, Marto JA. A chemoproteomic strategy for direct and proteome-wide covalent inhibitor target-site identification. J Am Chem Soc 2018; in press.
17. De Wispelarere M, Potisopon S, Li PC, Jang J, Ficarro SB, Clark MJ, Zhu X, Lian W, Kaplan JB, Pitts JD, Wales TE, Wang J, Engen JR, Marto JA, Gray NS, Yang PL. Inhibition of flaviviruses by targeting a conserved pocket on the viral envelope protein. Cell Chem Biol 2018;25:1006-16.
16. Gao Y, Zhang T, Terai H, Ficarro SB, Kwiatkowski N, Hao MF, Sharma B, Christensen CL, Chipumuro E, Wong KK, Marto JA, Hammerman PS, Gray NS, George RE. Overcoming resistance to the thz series of covalent transcriptional cdk inhibitors. Cell Chem Biol 2018;25:135-42.
15. Hatcher JM, Wu G, Zeng C, Zhu J, Meng F, Patel S, Wang W, Ficarro SB, Leggett AL, Powell CE, Marto JA, Zhang K, Ngo JCK, Fu XD, Zhang T, Gray NS. Srpkin-1: a covalent srpk1/2 inhibitor that potently coverts vegf from pro-angiogenic to anti-angiogenic isoform. Cell Chem Biol 2018;25:460-70.
14. Zeng M, Lu J, Li L, Feru F, Quan C, Gero TW, Ficarro SB, Xiong Y, Ambrogio C, Paranal RM, Catalano M, Shao J, Wong KK, Marto JA, Fisher ES, Janne PA, Scott DA, Westover KD, Gray NS. Potent and selective covalent quinazoline inhibitors of kras-g12c. Cell Chem Biol 2017;24:1005-16.
13. Tan L, Gurbani D, Weisberg EL, Hunter JC, Li L, Jones DS, Ficarro SB, Mowafy S, Tam CP, Rao S, Du G, Griffin JD, Sorger PK, Marto JA, Westover KD, Gray NS. Structure-guided development of covalent tak1 inhibitors. Bioorg Med Chem 2017;25:838-46.
12. Chen H, Coseno M, Ficarro SB, Mansueto MS, Meredith GK, Boissel S, Filman DJ, Marto JA, Hogle JM, Coen DM. A small covalent allosteric inhibitor of human cytomegalovirus dna polymerase subunit interactions. ACS Infectious Diseases 2017;10:112-8.
11. Ficarro SB, Browne CM, Card JD, Alexander WM, Zhang T, Park E, Paganon SD, Seo HS, Lamberto I, Eck MJ, Buhrlage SJ, Gray NS, Marto JA. Leveraging novel fragmentation pathways for improved identification and selective detection of targets modified by covalent probes. Anal Chem 2016;88:12248-54.
10. Harshbarger W, Gondi S, Ficarro SB, Hunter J, Udayakumar D, Gurbani D, Singer W, Liu Y, Marto JA, Westover KD. Structural basis of glutathione s-transferase p1 inhibition by hydrolyzed piperlongumine. J Biol Chem 2017; 292:112-20.
9. Zhang T, Kwiatkowski N, Olson CM, Clarke SED, Abraham BJ, Greifenberg AK, Ficarro SB, Elkins JM, Liang Y, Hannett NM, Manzi T, Bartkowiak B, Greenleaf AL, Marto JA, Geyer M, Bullock AN, Young RA, Gray NS. Covalent targeting of remote cysteine residues for the development of selective cdk12 and 13 inhibitors. Nat Chem Biol 2016;12:876-84.
8. Tan L, Akahane K, McNally R, Reyskens KMSE, Ficarro SB, Liu S, Herter-Sprie G, Koyama S, Pattison MJ, Labella K, Johannesen L, Akbay E, Wong K, Frank DA, Marto JA, Look TA, Arthur SJ, Eck MJ, Gray NS. Development of selective covalent jak3 inhibitors. J Med Chem 2015;58:6589-606.
7. Lim SM, Xie T, Westover KD, Ficarro SB, Tae HS, Gurbani D, Sim T, Marto JA, Janne PA, Crews CM, Gray NS. Development of small molecules targeting the pseudokinase her3. Bioorg Med Chem Lett 2015;25:3382-9.
6. Gridling M, Ficarro SB, Breitwieser FP, Song L, Parapatics K, Colinge J, Haura EB, Marto JA, Superti-Furga G, Bennett KL, Rix U. Identification of kinase inhibitor targets in lung cancer microenvironment by chemical and phosphoproteomics. Mol Cancer Therapeutics 2014;13:2751-62.
5. Xie T, Lim SM, Westover K, Dodge ME, Ercan D, Ficarro SB, Riddle SM, Marto JA, Janne PA, Crews CM, Gray NS. Pharmacological targeting of the pseudokinase her3. Nat Chem Biol 2014;10:1006-12.
4. Hunter J, Gurbani D, Ficarro SB, Carrasco M, Lim SM, Choi HG, Xie T, Marto JA, Chen JZ, Gray NS, Westover KD. Crystal structure of oncogenic k-ras g12c bound to the covalent active site inhibitor sml-8-73-1. Proc Natl Acad Sci U S A 2014; 111:8895-900.
3. Kwiatkowski N, Zhang T, Abraham B, Reddy J, Rahl P, Ficarro SB, Tesar B, McMillin D, Sanda T, Sim T, Kim ND, Look T, Mitsiades C, Brown J, Benes C, Marto JA, Young R, Gray N. Targeting transcriptional dependencies in cancer using a covalent cdk7 inhibitor. Nature 2014; 511:616-20.
2. Lim SM, Westover KD, Ficarro SB, Harrison RA, Choi HG, Pacold ME, Carrasco M, Hunter J, Kim ND, Xie T, Sim T, Janne P, Meyerson M, Marto JA, Engen JR, Gray NS. Therapeutic targeting of oncogenic k-ras by a covalent catalytic site inhibitor. Angew Chem 2014;53:199-204.
1. Zhang T, Vaquera FI, Niepel M, Zhang J, Ficarro SB, Machleidt T, Xie T, Marto JA, Kim ND, Sim T, Laughlin JD, Park H, LoGrasso PV, Patricelli M, Nomanbhoy TK, Sorger PK, Alessi DR, Gray NS. Discovery of potent and selective covalent inhibitors of jnk. Chem Biol 2012;19:140-54.