Prospective evaluation of structure-based simulations reveal their ability to predict the impact of kinase mutations on inhibitor binding

Sukrit Singh, Vytautas Gapsys, Matteo Aldeghi, David Schaller, Aziz M Rangwala, Jessica B White, Joseph P Bluck, Jenke Scheen, William G Glass, Jiaye Guo, Sikander Hayat, Bert L de Groot, Andrea Volkamer, Clara D Christ, Markus A Seeliger, John D Chodera.
[bioRxiv]

We show that alchemical free energy calculations have the potential to prospectively predict the impact of clinical kinase mutations on targeted kinase inhibitor binding.

INK4 tumor suppressor proteins mediate resistance to CDK4/6 kinase inhibitors

Li Q, Jiang B, Guo J, Shao H, Del Priore IS, Chang Q, Kudo R, Li Z, Razavi P, Liu B, Boghossian AS, Rees MG, Ronan MM, Roth JA, Donovan KA, Palafox M, Reis-Filho JS, de Stanchina E, Fischer ES, Rosen N, Serra V, Koff A, Chodera JD, Gray NS, and Chandardlapaty S
Cancer Discovery} 12:356, 2022 [DOI]

We demonstrate CDK6 causes drug resistance by binding INK4 proteins, and develop bifunctional degraders conjugating palbociclib with E3 ligands to overcome this mechanism of resistance.

Mutation in Abl kinase with altered drug binding kinetics indicates a novel mechanism of imatinib resistance

Agatha Lyczek, Benedict Tilman Berger, Aziz M Rangwala, YiTing Paung, Jessica Tom, Hannah Philipose, Jiaye Guo, Steven K Albanese, Matthew B Robers, Stefan Knapp, John D Chodera, Markus A Seeliger
Preprint ahead of publication: [bioRxiv]

Here, we characterize the biophysical mechanisms underlying mutants of Abl kinase associated with clinical drug resistance to targeted cancer therapies. We uncover a surprising novel mechanism of mutational resistance to kinase inhibitor therapy in which the off-rate for inhibitor unbinding is increased without affecting inhibitor affinity.