Abstract 1669: Identification of mutant KRas-Raf-1 binding disruptors

Abstract

Abstract Mutant KRas is a major driver of human cancer, yet currently no clinically approved therapies that directly target mutant KRas are available. In order to identify novel drugs that bind either mutant KRas or its effector Raf-1, we used alpha-screen and GST-pull down assays to identify disruptors of KRas G12D binding to the Ras-binding domain of Raf-1. From a novel, natural product-inspired chemical library called Complexity To Diversity (CTD), we have identified a series of 5 hits that belong to a family of gibberellic acid-derived compounds and 2 hits from a family of pleuromutilin-derived compounds. At present we are using Differential Scanning Fluorimeter (DSF) and Isothermal calorimetry (ITC) assays to determine whether these hits bind to KRas G12D or Raf-1 RBD. These studies may lead to identifying chemical probes that can be developed to target mutant KRas-driven cancers. Citation Format: Rajanikanth Vangipurapu, Liwei Chen, Perry Kennedy, Karen C. Morrison, Paul J. Hergenrother, Said M. Sebti. Identification of mutant KRas-Raf-1 binding disruptors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1669.