Discovery of SARxxxx92, a pan-PIM kinase inhibitor, efficacious in a KG1 tumor model

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127625. doi: 10.1016/j.bmcl.2020.127625.
Claude Barberis  1 ,  Paul Erdman  2 ,  Mark Czekaj  3 ,  Luke Fire  4 ,  James Pribish  3 ,  Elina Tserlin  5 ,  Sachin Maniar  3 ,  Joseph D Batchelor  3 ,  Jinyu Liu  3 ,  Vinod F Patel  6 ,  Andrew Hebert  7 ,  Mikhail Levit  7 ,  Anlai Wang  8 ,  Frank Sun  9 ,  Shih-Min A Huang  10
Affiliations
  • 1. IDD Medicinal Chemistry, Sanofi, 153 Second Avenue, Waltham MA 02451, United States. Electronic address: [email protected].
  • 2. IDD Medicinal Chemistry, Sanofi, 153 Second Avenue, Waltham MA 02451, United States; Present address: AbbVie, 100 Abbott Park Road, Abbott Park, IL 60064-3500, United States.
  • 3. IDD Medicinal Chemistry, Sanofi, 153 Second Avenue, Waltham MA 02451, United States.
  • 4. IDD Medicinal Chemistry, Sanofi, 153 Second Avenue, Waltham MA 02451, United States; Present address: Rakuten Medical, 11080 Roselle St, San Diego, CA 92121, United States.
  • 5. Present address: Qiagen, 561 Virginia Road, Concord, MA 01742, United States.
  • 6. Present address: TME Therapeutics, 3 Mossy Lane, Acton, MA 01720, United States.
  • 7. Oncology Biochemistry, Sanofi, 270 Albany Street, Cambridge MA 02139, United States.
  • 8. Oncology Biology, Sanofi, 270 Albany Street, Cambridge MA 02139, United States.
  • 9. Oncology Pharmacology, Sanofi, 640 Memorial Drive, Cambridge MA 02139, United States.
  • 10. Oncology Biology, Sanofi, 270 Albany Street, Cambridge MA 02139, United States; Present address: Bristol-Myers Squibb, 3551 Lawrenceville Princeton, Lawrence Township, NJ 08648, United States.
PMID: 33096160 DOI: 10.1016/j.bmcl.2020.127625
Abstract

N-substituted azaindoles were discovered as potent pan-PIM inhibitors. Lead optimization, guided by structure and focused on physico-chemical properties allowed us to solve inherent hERG and permeability liabilities, and provided compound 27, which subsequently impacted KG-1 tumor growth in a mouse model.

Keywords
AML; Cancer; Lead; PK/PD; Pan-PIM kinases; Tumor growth inhibition.
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