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

Communications Biology
Kevin HauserLingle Wang

Abstract

The therapeutic effect of targeted kinase inhibitors can be significantly reduced by intrinsic or acquired resistance mutations that modulate the affinity of the drug for the kinase. In cancer, the majority of missense mutations are rare, making it difficult to predict their impact on inhibitor affinity. This complicates the practice of precision medicine, pairing of patients with clinical trials, and development of next-generation inhibitors. Here, we examine the potential for alchemical free-energy calculations to predict how kinase mutations modulate inhibitor affinities to Abl, a major target in chronic myelogenous leukemia (CML). We find these calculations can achieve useful accuracy in predicting resistance for a set of eight FDA-approved kinase inhibitors across 144 clinically-identified point mutations, achieving a root mean square error in binding free energy changes of 1.1 0.9 1.3 kcal/mol (95% confidence interval) and correctly classifying mutations as resistant or susceptible with 88 82 93 % accuracy. Since these calculations are fast on modern GPUs, this benchmark establishes the potential for physical modeling to collaboratively support the rapid assessment and anticipation of the potential for patient...Continue Reading

References

Mar 26, 2003·Cell·Bhushan NagarJohn Kuriyan
Mar 19, 2004·Journal of Medicinal Chemistry·Richard A FriesnerPeter S Shenkin
Feb 16, 2005·Cancer Cell·Ellen WeisbergJames D Griffin
Oct 6, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Thomas O'HareBrian J Druker
Dec 8, 2006·Journal of Medicinal Chemistry·Julien MichelJonathan W Essex
Dec 26, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Simona SoveriniUNKNOWN GIMEMA Working Party on Chronic Myeloid Leukemia
Sep 28, 2007·Journal of Computer-aided Molecular Design·John C ShelleyMakoto Uchimaya
Oct 24, 2007·The Journal of Physical Chemistry. B·Michael R ShirtsVijay S Pande
Dec 14, 2007·Proceedings of the National Academy of Sciences of the United States of America·Ultan McDermottJeffrey Settleman
Apr 9, 2008·Current Pharmaceutical Biotechnology·Jan H Jensen
Apr 23, 2008·Proceedings of the National Academy of Sciences of the United States of America·Dian JiaoPengyu Ren
Dec 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·Yibing ShanDavid E Shaw
Oct 21, 2009·Journal of Computer-aided Molecular Design·Yvonne Connolly Martin
Jan 23, 2010·Nature Reviews. Cancer·Zachary A KnightKevan M Shokat
Jan 18, 2011·Expert Opinion on Investigational Drugs·Rina Barouch-Bentov, Karsten Sauer
Feb 1, 2011·Journal of Chemical Theory and Computation·James LuccarelliWilliam L Jorgensen
Feb 26, 2011·Current Opinion in Structural Biology·John D ChoderaVijay S Pande
Jul 26, 2011·Journal of Chemical Information and Modeling·Chaya RappMatthew P Jacobson
Nov 1, 2011·Nature Biotechnology·Mindy I DavisPatrick P Zarrinkar
Feb 7, 2012·Proceedings of the National Academy of Sciences of the United States of America·Lingle WangRichard A Friesner
Oct 30, 2012·The Biochemical Journal·Jin H ParkRavi Radhakrishnan
Jul 9, 2013·Journal of Computational Chemistry·Jing Huang, Alexander D MacKerell
Jul 31, 2013·Quarterly Reviews of Biophysics·Alexey V Onufriev, Emil Alexov
Sep 26, 2013·Nature Reviews. Cancer·Caitriona HolohanPatrick G Johnston
Nov 23, 2013·Cancer Discovery·Eliezer M Van AllenUNKNOWN Dermatologic Cooperative Oncology Group of Germany (DeCOG)
Dec 18, 2013·Annual Review of Physical Chemistry·Omar DemerdashTeresa Head-Gordon
Mar 4, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Sara C Meyer, Ross L Levine
Jun 11, 2014·Nucleic Acids Research·Alexandre MelnikovTarjei S Mikkelsen
Sep 10, 2014·Cancers·Genevieve HousmanSibaji Sarkar
Feb 11, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Amanda J Redig, Pasi A Jänne
May 30, 2015·Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy·Michael JuchumStefan A Laufer
Sep 16, 2015·Proceedings of the National Academy of Sciences of the United States of America·Monika A DavareBrian J Druker

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Citations

Mar 20, 2019·PloS One·Christopher NegronGuillermo Del Angel
Oct 3, 2019·The Journal of Chemical Physics·Rajat K Pal, Emilio Gallicchio
Apr 11, 2020·International Journal of Molecular Sciences·Swagata PahariEmil Alexov
Feb 12, 2021·Journal of Hematology & Oncology·Sitong YueDaichao Wu
Oct 23, 2020·The Journal of Chemical Physics·Peter WirnsbergerCharles Blundell
Jul 22, 2020·Chemical Reviews·Richard A WardPaul D Smith
Oct 30, 2020·Journal of Chemical Information and Modeling·Steven K AlbaneseLingle Wang
Sep 5, 2019·ACS Central Science·Alice E Brankin, Philip W Fowler
Sep 5, 2019·ACS Central Science·Matteo AldeghiBert L de Groot
Jan 17, 2019·ACS Central Science·Matteo AldeghiBert L de Groot
Aug 14, 2020·Journal of Chemical Information and Modeling·Hiraku OshimaYuji Sugita

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Methods Mentioned

BETA
X-ray

Software Mentioned

Prime
CHARMM
FEP
Force Field Builder
MMGBSA
PROPKA
SP
NIVIDA
MM
Epik

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