2. Academic Validation
  3. Identification of Structurally Novel KRASG12C Inhibitors through Covalent DNA-Encoded Library Screening

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

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.

Figures
Products