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Discovery of BMS-986260, a Potent, Selective, and Orally Bioavailable TGFβR1 Inhibitor as an Immuno-oncology Agent

  • Upender Velaparthi*
    Upender Velaparthi
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
    *Tel: +1-609-252-6716. Email: [email protected]
  • Chetan Padmakar Darne
    Chetan Padmakar Darne
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Jayakumar Warrier
    Jayakumar Warrier
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Peiying Liu
    Peiying Liu
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
    More by Peiying Liu
  • Hasibur Rahaman
    Hasibur Rahaman
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Karen Augustine-Rauch
    Karen Augustine-Rauch
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Karen Parrish
    Karen Parrish
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Zheng Yang
    Zheng Yang
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
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  • Jesse Swanson
    Jesse Swanson
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Jennifer Brown
    Jennifer Brown
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Gopal Dhar
    Gopal Dhar
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
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  • Aravind Anandam
    Aravind Anandam
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Vinay K. Holenarsipur
    Vinay K. Holenarsipur
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Kamalavenkatesh Palanisamy
    Kamalavenkatesh Palanisamy
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Barri S. Wautlet
    Barri S. Wautlet
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Mark P. Fereshteh
    Mark P. Fereshteh
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Jonathan Lippy
    Jonathan Lippy
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Andrew J. Tebben
    Andrew J. Tebben
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Steven Sheriff
    Steven Sheriff
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Max Ruzanov
    Max Ruzanov
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
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  • Chunhong Yan
    Chunhong Yan
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
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  • Anuradha Gupta
    Anuradha Gupta
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Arun Kumar Gupta
    Arun Kumar Gupta
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Muthalagu Vetrichelvan
    Muthalagu Vetrichelvan
    Biocon Bristol-Myers Squibb R & D Center, Biocon Park, Jigani Link Road, Bangalore, KA 560099, India
  • Arvind Mathur
    Arvind Mathur
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Marina Gelman
    Marina Gelman
    Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States
  • Rajinder Singh
    Rajinder Singh
    Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States
  • Todd Kinsella
    Todd Kinsella
    Rigel Pharmaceuticals, Inc., 1180 Veterans Boulevard, South San Francisco, California 94080, United States
  • Anwar Murtaza
    Anwar Murtaza
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Joseph Fargnoli
    Joseph Fargnoli
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
  • Gregory Vite
    Gregory Vite
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
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  • , and 
  • Robert M. Borzilleri
    Robert M. Borzilleri
    Bristol-Myers Squibb Research & Development, P.O. Box 4000, Princeton, New Jersey 08543, United States
Cite this: ACS Med. Chem. Lett. 2020, 11, 2, 172–178
Publication Date (Web):January 28, 2020
https://doi.org/10.1021/acsmedchemlett.9b00552
Copyright © 2020 American Chemical Society
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Supporting Info (1)»

Abstract

Abstract Image

Novel imidazole-based TGFβR1 inhibitors were identified and optimized for potency, selectivity, and pharmacokinetic and physicochemical characteristics. Herein, we report the discovery, optimization, and evaluation of a potent, selective, and orally bioavailable TGFβR1 inhibitor, 10 (BMS-986260). This compound demonstrated functional activity in multiple TGFβ-dependent cellular assays, excellent kinome selectivity, favorable pharmacokinetic properties, and curative in vivo efficacy in combination with anti-PD-1 antibody in murine colorectal cancer (CRC) models. Since daily dosing of TGFβR1 inhibitors is known to cause class-based cardiovascular (CV) toxicities in preclinical species, a dosing holiday schedule in the anti-PD-1 combination efficacy studies was explored. An intermittent dosing regimen of 3 days on and 4 days off allowed mitigation of CV toxicities in one month dog and rat toxicology studies and also provided similar efficacy as once daily dosing.

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Cited By

This article is cited by 9 publications.

  1. Yong Zhang, Karen E. Parrish, David R. Tortolani, Michael A. Poss, Audris Huang, Honghe Wan, Ashok V. Purandare, Andrew F. Donnell, James Kempson, Xiaoping Hou, Joseph Pawluczyk, Shiuhang Yip, Emily Luk, Nimmi Raghavan, Jesse Swanson, James Smalley, Anwar Murtaza, Zheng Yang, Karen Augustine-Rauch, Louis J. Lombardo, Robert Borzilleri. Long-Acting Tumor-Activated Prodrug of a TGFβR Inhibitor. Journal of Medicinal Chemistry 2021, 64 (21) , 15787-15798. https://doi.org/10.1021/acs.jmedchem.0c02043
  2. Shohei Miwa, Masahiro Yokota, Yoshifumi Ueyama, Katsuya Maeda, Yosuke Ogoshi, Noriyoshi Seki, Naoki Ogawa, Jun Nishihata, Akihiro Nomura, Tsuyoshi Adachi, Yuki Kitao, Keisuke Nozawa, Tomohiro Ishikawa, Yutaka Ukaji, Makoto Shiozaki. Discovery of Selective Transforming Growth Factor β Type II Receptor Inhibitors as Antifibrosis Agents. ACS Medicinal Chemistry Letters 2021, 12 (5) , 745-751. https://doi.org/10.1021/acsmedchemlett.0c00679
  3. Muthalagu Vetrichelvan, Souvik Rakshit, Sathishkumar Chandrasekaran, Karthikeyan Chinnakalai, Chetan Padmakar Darne, Dyamanna Doddalingappa, Indasi Gopikumar, Anuradha Gupta, Arun Kumar Gupta, Ananta Karmakar, Thirumalai Lakshminarasimhan, David K. Leahy, Senthil Palani, Vignesh Radhakrishnan, Richard Rampulla, Antony Savarimuthu, Varadharajan Subramanian, Upender Velaparthi, Jayakumar Warrier, Martin D. Eastgate, Robert M. Borzilleri, Arvind Mathur, Rajappa Vaidyanathan. Development of a Scalable Synthesis of the Small Molecule TGFβR1 Inhibitor BMS-986260. Organic Process Research & Development 2020, 24 (7) , 1310-1320. https://doi.org/10.1021/acs.oprd.0c00232
  4. Li Chen, Xiaoying Jiang, Yuanheng Li, Qiqi Zhang, Qing Li, Xiaoyan Zhang, Meng Zhang, Qiongfang Yu, Dian Gao. How to overcome tumor resistance to anti-PD-1/PD-L1 therapy by immunotherapy modifying the tumor microenvironment in MSS CRC. Clinical Immunology 2022, 237 , 108962. https://doi.org/10.1016/j.clim.2022.108962
  5. Nathan Bedard, Alessandra Fistrovich, Kevin Schofield, Arthur Shaw, Christopher Hulme. Recent Applications of Multicomponent Reactions Toward Heterocyclic Drug Discovery. 2022,,, 339-409. https://doi.org/10.1002/9783527832439.ch9
  6. Ahmed El Akkaoui, Jamal Koubachi, Gérald Guillaumet, Saïd El Kazzouli. Synthesis and Functionalization of Imidazo[1,2‐ b ]Pyridazine by Means of Metal‐Catalyzed Cross‐Coupling Reactions. ChemistrySelect 2021, 6 (34) , 8985-9011. https://doi.org/10.1002/slct.202101636
  7. Karen E. Parrish, Jesse Swanson, Lihong Cheng, Emily Luk, Paul Stetsko, James Smalley, Yue‐Zhong Shu, Jinwen Huang, Jonathan G. Pabalan, Yongnian Sun, Tatyana Zvyaga, Mary Ellen Cvijic, James Burke, Robert Borzilleri, Anwar Murtaza, Karen Augustine, Zheng Yang. Pharmacodynamics‐based approach for efficacious human dose projection of BMS‐986260, a small molecule transforming growth factor beta receptor 1 inhibitor. Biopharmaceutics & Drug Disposition 2021, 42 (4) , 137-149. https://doi.org/10.1002/bdd.2256
  8. K. Alison Rinderspacher. Six-membered ring systems: diazines and benzo derivatives. 2021,,, 381-439. https://doi.org/10.1016/B978-0-323-98410-2.00013-8
  9. Guofeng Xu, Yan Zhang, Hai Wang, Zhuang Guo, Xiaowei Wang, Xue Li, Shaohua Chang, Tianwen Sun, Zhuangzhuang Yu, Tianwei Xu, Liwen Zhao, Yazhou Wang, Wenying Yu. Synthesis and biological evaluation of 4-(pyridin-4-oxy)-3-(3,3-difluorocyclobutyl)-pyrazole derivatives as novel potent transforming growth factor-β type 1 receptor inhibitors. European Journal of Medicinal Chemistry 2020, 198 , 112354. https://doi.org/10.1016/j.ejmech.2020.112354

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