Identification of Structurally Novel KRASG12C Inhibitors through Covalent DNA-Encoded Library Screening

  • J Med Chem. 2025 Feb 27;68(4):4801-4817. doi: 10.1021/acs.jmedchem.4c03071.
David Huang ,  Francesco Manoni ,  Zhen Sun  1 ,  Rongfeng Liu  1 ,  Jennifer R Allen ,  Abhisek Banerjee  2 ,  Victor J Cee ,  Josephine Eshon ,  Michael J Frohn ,  Matthew R Kaller ,  Heejun Lee ,  Cui Li  1 ,  Xun Li  1 ,  Patricia Lopez ,  Vu Ma ,  Jose M Medina ,  Christopher Mohr ,  Olga A Mukhina ,  Alexander J Pickrell ,  John Stellwagen ,  Wenting Wu  1 ,  Wenhan Zhang ,  Kai Zhu ,  Upendra P Dahal  3 ,  Liaoyuan A Hu  1 ,  Monica Leavitt ,  Wencui Li  1 ,  Yu Li ,  Yingli Ma  1 ,  Karen Rex ,  Anne Y Saiki ,  Paul Wang ,  Yaping Sun  1 ,  Dongcheng Dai  1 ,  Nuria A Tamayo ,  Brian A Lanman
Affiliations
  • 1. Department of Therapeutic Discovery, Amgen Asia R&D Center, Amgen Research, 4560 Jinke Road, Pudong, Shanghai 201210, P. R. China.
  • 2. Syngene Amgen Research & Development Center (SARC), Syngene International Ltd., Biocon Park, Jigani Link Road, Bengaluru 560099, India.
  • 3. Department of Pharmacokinetics and Drug Metabolism, Amgen Research, 750 Gateway Boulevard, Suite 100, South San Francisco, California 94080, United States.
PMID: 39930787 DOI: 10.1021/acs.jmedchem.4c03071
Abstract

Covalent inhibition of the KRASG12C oncoprotein has emerged as a promising therapeutic approach for the treatment of nonsmall cell Lung Cancer (NSCLC). The identification of KRASG12C inhibitors has typically relied on the high-throughput screening (HTS) of libraries of cysteine-reactive small molecules or on the attachment of cysteine-reactive warheads to noncovalent Binders of KRAS. Such screening approaches have historically been limited in the size and diversity of molecules that could be effectively screened. DNA-encoded library (DEL) screening has emerged as a promising approach to accelerate the preparation and screening of incredibly large and diverse chemical libraries. Here, we describe the design and synthesis of a covalent DEL to screen ∼16 million compounds against KRASG12C. We additionally describe the hit identification, validation, and structure-based optimization that culminated in the identification of a series of structurally novel, potent, and selective covalent inhibitors of KRASG12C with good pharmacokinetic profiles and promising in vivo pharmacodynamic effects.

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