Abstract

Abstract Many tumors are driven by oncogenic kinases. While a majority of the most prevalent oncogenic kinases currently have existing targeted therapies available, most of the molecules were not designed to be CNS penetrant and are therefore unable to control CNS metastatic tumors. By employing principles for the design of CNS penetrant molecules, we discovered two brain-penetrant BRAF inhibitors, which both progressed into clinical trials. The first candidate, ARRY-461, was designed to inhibit class I mutant BRAF V600E tumors. The second candidate, ARRY-440, was designed to inhibit class I, II, III, and indel mutant BRAF tumors. Additionally, ARRY-440 was designed to overcome both the paradoxical activation of BRAF as well as inhibit mBRAF:wtCRAF heterodimers, two features that most 1st generation BRAF V600E inhibitors lack. Finally, we were pleased to see that ARRY-440 led to clinical responses in a variety of different BRAF V600E tumors, including in some tumors that harbored both a BRAF V600E mutation and an oncogenic NRAS mutation. Citation Format: Dean Kahn. Discovery of brain-penetrant inhibitors for the treatment of BRAF mutant tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA020.

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