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.

Is structure based drug design ready for selectivity optimization?

Steven K. Albanese, John D. Chodera, Andrea Volkamer, Simon Keng, Robert Abel, and Lingle Wang
Journal of Chemical Informatics and Modeling [DOI] [bioRxiv] [GitHub]

We asked whether the similarity of binding sites in related kinases might result in a fortuitous cancellation of errors in using alchemical free energy calculations to predict kinase inhibitor selectivities. Surprisingly, we find that even distantly related kinases have sufficient correlation in their errors that predicting changes in selectivity can be much more accurate than predicting changes in potency due to this effect, and show how this could lead to large reductions in the number of molecules that must be synthesized to achieve a desired selectivity goal.

A small-molecule pan-Id antagonist inhibits pathologic ocular neovascularization

Paulina M. Wojnarowicz, Raquel Lima e Silva, Masayuki Ohanka, Sang Bae Lee, Yvette Chin, Anita Kulukian, Sung-Hee Chang, Bina Desai, Marta Garcia Escolano, Riddhi Shah, Marta Garcia-Cao, Sijia Xu, Rashmi Thakar, Yehuda Goldgur, Meredith A. Miller, Ouathek Ouerfelli, Guangli Yang, Tsutomu Arakawa, Steven K. Albanese, William A. Garland, Glenn Stoller, Jaideep Chaudhary, Rajesh Soni, John Philip, Ronald C. Hendrickson, Antonio Iavarone, Andrew J. Dannenberg, John D. Chodera, Nikola Pavletich, Anna Lasorella, Peter A. Campochiaro, and Robert Benezra
Cell Reports 29:62, 2019 [DOI] [PDF]

We report the discovery and characterization of a small molecule, AGX51, with the surprising ability to inhibit the interaction of Id1 with E47, which leads to ubiquitin-mediated degradation of Ids.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Gerard Minuesa, Steven K Albanese, Arthur Chow, Alexandra Schurer, Sun-Mi Park, Christina Z. Rotsides, James Taggart, Andrea Rizzi, Levi N. Naden, Timothy Chou, Saroj Gourkanti, Daniel Cappel, Maria C Passarelli, Lauren Fairchild, Carolina Adura, Fraser J Glickman, Jessica Schulman, Christopher Famulare, Minal Patel, Joseph K Eibl, Gregory M Ross, Derek S Tan, Christina S Leslie, Thijs Beuming, Yehuda Goldgur, John D Chodera, Michael G Kharas
Nature Communications 10:2691, 2019. [DOI] [bioRxiv] [GitHub] [MSKCC blog post]

We use absolute alchemical free energy calculations to identify the likely interaction site for a small hydrophobic ligand that shows activity against MUSASHI in AML.

Acquired resistance to IDH inhibition through trans or cis dimer-interface mutations

Andrew M. Intlekofer,  Alan H. Shih,  Bo Wang,  Abbas Nazir,  Ariën S. Rustenburg,  Steven K. Albanese, Minal Patel, Christopher Famulare, Fabian M. Correa, Naofumi Takemoto, Vidushi Durani, Hui Liu, Justin Taylor, Noushin Farnoud, Elli Papaemmanuil, Justin R. Cross, Martin S. Tallman, Maria E. Arcila, Mikhail Roshal, Gregory A. Petsko, Bin Wu, Sung Choe, Zenon D. Konteatis, Scott A. Biller, John D. Chodera, Craig B. Thompson, Ross L. Levine, and Eytan M. Stein
Nature 559:125, 2018. [DOI] [PDF]

We probe the biochemical and biophysical mechanisms underlying an unusual set of clinical resistance mutations that appeared in trans in the IDH2 dimer interface in cancer patients treated with IDH2 inhibitors.

Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations

Kevin Hauser, Christopher Negron, Steven K. Albanese, Soumya Ray, Thomas Steinbrecher, Robert Abel, John D. Chodera, and Lingle Wang.
Communications Biology 1:70, 2018 [DOI] [PDF] [input files and analysis scripts]

In our first collaborative paper with Schrödinger, we present the first comprehensive benchmark assessing the ability for alchemical free energy calculations to predict clinical mutational resistance or susceptibility to targeted kinase inhibitors using the well-studied kinase Abl, the target of therapy for chronic myelogenous leukemia (CML).

Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin

Xu Jianing, Pham CG, Albanese SK, Dong Yiyu, Oyama T, Lee CH, Rodrik-Outmezguine V, Yao Z, Han S, Chen D, Parton DL, Chodera JD, Rosen N, Cheng EH, and Hsieh J. Journal of Clinical Investigation 126:3526, 2016. [DOI] [PDF]

In work with the James Hsieh lab at MSKCC, we examine the surprising origin of how different clinically-identified cancer-associated mutations in MTOR activate the kinase through distinct mechanisms.