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Investigating therapeutic chemotypes by merging functional genomics and drug design

Abstract

Biologically active compounds exert their effects on living systems by binding to and modulating particular nodes among a vast network of macromolecules within the cell. The complexity of cellular machinery renders understanding which nodes are affected (i.e. direct targets or related pathways) a major challenge in the development of novel therapeutics. Furthermore, compounds of therapeutic interest might interact with cellular processes that were previously unknown, providing an opportunity for biological discovery in addition to informing drug chemical optimization. Here, we combined CRISPR (clustered regularly interspaced short palindromic repeats)-based functional genomics technologies with an atomistic approach to drug design across two important therapeutic targets, KRASG12C and MTOR. Using covalent switch-II pocket (S-IIP) inhibitors of KRASG12C, we nominated multiple genetic targets that could be co-inhibited to increase KRASG12C target engagement or block residual cancer survival pathways. We then applied a similar approach to uncover chemical-genetic interactions with a prototype bitopic MTOR inhibitor (molecular weight: 1784 g/mol), leading to the identification of an endogenous chemical uptake pathway involving interferon-induced transmembrane (IFITM) proteins. These proteins facilitate the cellular entry of diverse linked chemotypes, expanding cell permeable chemical space beyond traditional guidelines for drug-like molecules (e.g. Lipinski’s rule of five). These findings demonstrate the mutual utility of a combined functional genomics and chemical approach toward the development of therapeutics with novel mechanisms of action.

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