Abstract 5165: Novel RAS inhibitors DC070-547 and ADT-006 potently and selectively inhibit the growth of pancreatic tumor cells harboring constitutively activated RAS by blocking RAS-effector binding and signaling

Abstract

Abstract Gain-in-function mutations in RAS genes cause constitutive activation of RAS and induction of downstream signaling pathways that drive tumor cell proliferation, survival, and metastasis. Such driver mutations occur in over 90% of pancreatic ductal adenocarcinomas (PDACs), making RAS an attractive cancer target. However, RAS is considered “undruggable”, given the lack of suitable surfaces on the protein for small molecule binding, as well as its high affinity for GTP binding. A phenotypic assay was developed to screen a library of indene derivatives for growth inhibitory activity in tumor cells harboring constitutively active RAS versus tumor cells with low levels of active RAS. A novel compound series was identified that potently and selectively inhibits the growth of tumor cells with constitutively active RAS, while having minimal effects on tumor cells lacking constitutively active RAS or cells derived from normal tissues. Chemical optimization resulted in a drug development candidate, DC070-547, and several back-up analogs (e.g. ADT-006), which showed strong antitumor activity at doses that do not cause any discernible toxicity in preclinical mouse models. Here we report DC070-547 and ADT-006 inhibited the growth of PDAC cells with IC50 values of approximately 2 nM and 20 nM, respectively, in MIA PaCa-2 cells harboring constitutively active RAS and greater than 350-fold selectivity over BxPC-3 cells, which lack constitutively active RAS. Both compounds also decreased the clonogenic potential of MIA PaCa-2 cells at concentrations that inhibit their growth. Within the same low nanomolar concentration range, treatment of recombinant human K-RAS, MIA PaCa-2 cell lysates, and intact MIA PaCa-2 cells blocked RAS-effector interactions as evident by performing active RAS pull-down assays using GST-RAF1-RBD/glutathione agarose. Treatment of intact MIA PaCa-2 cells also inhibited RAF/MAPK and PI3K/AKT phosphorylation within the same concentration range. These results demonstrate that DC070-547 and ADT-006 inhibit PDAC cell growth by blocking RAS-effector interactions, supporting further evaluation of this novel class of RAS inhibitors for the treatment of pancreatic cancer, as well as other RAS-driven cancers. Citation Format: Tyler E. Mattox, Kevin J. Lee, Xi Chen, Jacob Valiyaveettil, Luciana Madeira da Silva, Ashley S. Lindsey, Adam B. Keeton, Bing Zhu, Michael Boyd, Gary A. Piazza. Novel RAS inhibitors DC070-547 and ADT-006 potently and selectively inhibit the growth of pancreatic tumor cells harboring constitutively activated RAS by blocking RAS-effector binding and signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5165. doi:10.1158/1538-7445.AM2017-5165