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PIPELINE > TRIAL OVERVIEW

Trial Information
Molecule Overview
SMARCA2 (BRM) Inhibitor
LY4050784
SMARCA2 (BRM) MOA

Zhang B, et al1; Jancewicz I, et al2; Papillon JPN, et al3; Helming KC, et al4; Wilson BG, et al5; Hoffman GR, et al6

Target

BAF (mSWI/SNF) is a chromatin remodeling complex comprised of multiprotein subunits. BAF requires either SMARCA2 (BRM) or SMARCA4 (BRG1), mutually exclusive ATPase subunits, for chromatin remodeling to occur. Inhibiting SMARCA2 in SMARCA4-deficient cancer is expected to cause synthetic lethality.2 SMARCA4 mutations are observed in multiple tumor types, including up to 11% in non-small cell lung cancers.7

Molecule
LY4050784 is a first-in-class, potent, selective, oral SMARCA2 (BRM) inhibitor with greater than 30-fold selectivity for SMARCA2 (BRM) over SMARCA4 (BRG1).8 Preclinical models have demonstrated tumor regression or tumor growth inhibition in SMARCA4-mutant cell lines containing KRAS, TP53, STK11, and KEAP1.8 The competitive pharmacokinetic properties and preclinical data support further advancements into clinical testing.
Clinical Development

LY4050784 is being studied in clinical trials in patients with non-small cell lung cancer and other solid tumors.

References

  1. Zhang B, et al. Nat Commun. 2021;12(1):1275.
  2. Jancewicz I, et al. Epigenetics Chromatin. 2019;12(1):68.
  3. Papillon JPN, et al. J Med Chem. 2018;61(22):10155-10172.
  4. Helming KC, et al. Cancer Cell. 2014;26(3):309-317.
  5. Wilson BG, et al. Mol Cell Biol. 2014;34(6):1136-1144.
  6. Hoffman GR, et al. Proc Natl Acad Sci U S A. 2014;111(8):3128-3133.
  7. Dagogo-Jack I, et al. J Thorac Oncol. 2020;15(5):766-776.
  8. Lee JY, et al. Discovery of selective BRM (SMARCA2) ATPase inhibitors for the treatment of BRG1 (SMARCA4) mutant cancers. Presented at: AACR Annual Meeting; April 5-10, 2024; San Diego, CA.
SMARCA2 (BRM) MOA2

Zhang B, et al1; Jancewicz I, et al2; Papillon JPN, et al3; Helming KC, et al4; Wilson BG, et al5; Hoffman GR, et al6

For information on trial enrollment, locations, and more, call 1-800-545-5979.
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