Prof. Peter Tonge - Kinetic Selectivity – A Missed Opportunity in Drug Discovery? - IPBS-Toulouse, Seminar Room

Peter Tonge

Center for Advanced Study of Drug Action, Departments of Chemistry and Radiology, Stony Brook University, Stony Brook NY 11794-3400

Kinetic Selectivity – A Missed Opportunity in Drug Discovery?

Selectivity is classically defined as the relative affinity of a drug for the desired target compared to the affinity of the drug for off-target proteins. Together with high affinity, selectivity is one of the most sought-after properties of drug molecules. However, there are actually two types of selectivity: thermodynamic selectivity which is based on relative affinities, and kinetic selectivity, which is based on the relative rates for binding to (kon) and dissociation from (koff) the desired target compared to off-target proteins. Since thermodynamics and kinetics are two sides of the same coin, there can be kinetic selectivity even if there is no thermodynamic selectivity. The presentation will introduce the potential benefits of kinetic selectivity, factors such as target vulnerability, the rate of target resynthesis and drug pharmacokinetics that impact the utility of kinetic selectivity, and a discussion of how kinetic selectivity can be evaluated and deployed. Systems that will be covered will include long residence time inhibitors of antibacterial drug targets and the post-antibiotic effect, and inhibitors and degraders (PROTACs) of the oncology target Bruton’s tyrosine kinase (BTK).

Selected publications

(1) Wang, M.; He, Y.; Cohen, S. A.; Strohm, A. R.; Shetye, G.; Franzblau, S. G.; Walker, S. G.; Alley, M. R. K.; Tonge, P. J. Selectivity of the Time-Dependent M. tuberculosis LeuRS Inhibitor Ganfeborole Is Driven by Target Vulnerability ACS Chem Biol, 2025, 20, 2955-2965. DOI: 10.1021/acschembio.5c00705
(2) Gilberti, A. L.; Tu, M. M.; Rachwalski, K.; Ali, M. I.; Cohen, S. A.; Akoglu, M.; Pollard-Kerning, A. C.; Tolentino Collado, J.; Sabbah, A.; Abou Said, F.; Dela, P.; Walker, S. G.; Haley, J. D.; Brown, E. D.; Tonge, P. J. Identifying Modulators of the Post-Antibiotic Effect ACS Infect Dis, 2025, 11, 2542-2552. DOI: 10.1021/acsinfecdis.5c00424
(3) Corrionero, A.; Zhang, X.; Alfonso, P.; Morris, P. J.; Klumpp-Thomas, C.; Melani, C.; McKnight, C.; Phelan, J. D.; Holland, D.; Wilson, K.; Hoyt, S. B.; Roschewski, M.; Tonge, P. J.; Wilson, W.; Ceribelli, M.; Staudt, L. M.; Thomas, C. J. An Assessment of Kinase Selectivity, Enzyme Inhibition Kinetics and in Vitro Activity for Several Bruton Tyrosine Kinase (BTK) Inhibitors ACS Pharmacol Transl Sci, 2025, 8, 4312-4325. DOI: 10.1021/acsptsci.5c00412
(4) Bravo, E., Jr.; Li, Y.; Lin, D. Y.; Srinivasan, B.; Barone, M.; Li, S. X.; DelloRusso, F.; Rahiyanath, A. S.; Corrionero, A.; Alfonso, P.; Prendiville, N.; Kozakov, D.; Andreotti, A. H.; Tonge, P. J. Modulating the Binding Kinetics of Bruton's Tyrosine Kinase Inhibitors through Transition-State Effects J Am Chem Soc, 2025, 147, 27876-27891. DOI: 10.1021/jacs.5c07063
(5) Li, Y. Q.; Lannigan, W. G.; Davoodi, S.; Daryaee, F.; Corrionero, A.; Alfonso, P.; Rodriguez-Santamaria, J. A.; Wang, N.; Haley, J. D.; Tonge, P. J. Discovery of Novel Bruton's Tyrosine Kinase PROTACs with Enhanced Selectivity and Cellular Efficacy J Med Chem, 2023, 66, 7454-7474. DOI: 10.1021/acs.jmedchem.3c00176
(6) Basak, S.; Li, Y.; Tao, S.; Daryaee, F.; Merino, J.; Gu, C.; Delker, S. L.; Phan, J. N.; Edwards, T. E.; Walker, S. G.; Tonge, P. J. Structure-Kinetic Relationship Studies for the Development of Long Residence Time LpxC Inhibitors J Med Chem, 2022, 65, 11854-11875. DOI: 10.1021/acs.jmedchem.2c00974
(7) Basu, R.; Wang, N.; Basak, S.; Daryaee, F.; Babar, M.; Allen, E. K.; Walker, S. G.; Haley, J. D.; Tonge, P. J. Impact of target turnover on the translation of drug-target residence time to time-dependent antibacterial activity ACS Infect Dis, 2021, 7, 2755-2763. DOI: 10.1021/acsinfecdis.1c00317
(8) Tonge, P. J. Drug-target kinetics in drug discovery ACS Chem Neurosci, 2018, 9, 29-39. DOI: 10.1021/acschemneuro.7b00185

Biosketch

Dr. Tonge is a Distinguished Professor of Chemistry at Stony Brook University, and the Director of the Center for Advanced Study of Drug Action. He is also a Visiting Professor at the University of Rochester and a Visiting Scientist at the Broad Institute of MIT and Harvard. The primary focus of his program involves the integration of drug-target binding kinetics into predictions of drug activity to improve the selection and optimization of drug candidates. Projects in his lab include the design, synthesis and evaluation of time-dependent enzyme inhibitors, the synthesis and evaluation of targeted protein degraders, and studies to elucidate how photoreceptors control and respond to the absorption of light. The translation of time-dependent enzyme inhibition or protein degradation to in vivo efficacy depends on target vulnerability, and a central goal of his program is to develop vulnerability functions for targets particularly in antibacterial and oncology drug space. His awards include an Alfred P. Sloan Research Fellowship, and a Fellowship from the Pharmaceutical Research and Manufacturers of America (PhRMA) which funded a sabbatical at Genentech.