Discovery of a Bicyclic Peptidyl Pan-Ras Inhibitor

  • J Med Chem. 2021 Sep 9;64(17):13038-13053. doi: 10.1021/acs.jmedchem.1c01130.
Marina Buyanova  1 ,  Shurui Cai  2 ,  Jahan Cooper  1 ,  Curran Rhodes  1 ,  Heba Salim  1 ,  Ashweta Sahni  1 ,  Punit Upadhyaya  1 ,  Rui Yang  1 ,  Amar Sarkar  1 ,  Na Li  2 ,  Qi-En Wang  2  3 ,  Dehua Pei  1  3
Affiliations
  • 1. Department of Chemistry and Biochemistry, The Ohio State University, Columbus, Ohio 43210, United States.
  • 2. Department of Radiation Oncology, The Ohio State University, Columbus, Ohio 43210, United States.
  • 3. Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210, United States.
PMID: 34415745 DOI: 10.1021/acs.jmedchem.1c01130
Abstract

The Ras subfamily of small GTPases is mutated in ∼30% of human cancers and represents compelling yet challenging Anticancer drug targets owing to their flat protein surface. We previously reported a bicyclic peptidyl inhibitor, cyclorasin B3, which binds selectively to Ras-GTP with modest affinity and blocks its interaction with downstream effector proteins in vitro but lacks cell permeability or biological activity. In this study, optimization of B3 yielded a potent pan-Ras inhibitor, cyclorasin B4-27, which binds selectively to the GTP-bound forms of wild-type and mutant Ras isoforms (KD = 21 nM for KRasG12V-GppNHp) and is highly cell-permeable and metabolically stable (serum t1/2 > 24 h). B4-27 inhibits Ras signaling in vitro and in vivo by blocking Ras from interacting with downstream effector proteins and induces Apoptosis of Ras-mutant Cancer cells. When administered systemically (i.v.), B4-27 suppressed tumor growth in two different mouse xenograft models at 1-5 mg/kg of daily doses.