Activating mutations and genetic alterations in protein kinase encoding genes, such as EGFR, HER2, KRAS, BRAF, ALK and ROS1, have been demonstrated to be oncogenic ?drivers? in human lung cancer. Protein kinases harboring such activating alterations have proven to be amenable to inhibition by small molecule inhibitors of enzymatic activity. During the previous funding period this Core was highly productive in establishing new inhibitors and helped advance concepts for developing mutant-selective EGFR inhibitors and first-in-class inhibitors of DDR1 and DDR2. In addition, we developed the first allosteric inhibitors of EGFR which can overcome resistance mutations that emerge in the ATP-binding site. Unfortunately, despite dramatic clinical response to targeted agents, resistance inevitably emerges. The goal of the Chemistry Core (Core A) is to address this challenge by advancing fundamentally new pharmacological approaches for these targets, including the development of novel allosteric inhibitors. In particular, we will exploit a recently described approach involving the development of bi-valent small molecules that induce ubiquitination and subsequent proteosomal degradation of targets of interest. We will use ligands related to thalidomide, which can recruit the E3 ligase, cereblon, that we call ?selective degraders? (they are also sometimes called PROTACs or degronimids). The Core will develop, refine and provide access to inhibitors and clinical stage compounds required by the Program investigators. The Core will accomplish this goal by collaborating with all three Research Projects and the other Resource Cores to identify and optimize selective degraders for mutant forms of EGFR (Project 1; Leader, Jnne), c-RAF & Mek1/2 (Project 2; Leader, Hahn and co-Leader, Barbie), and transcriptional cyclin dependent kinases (CDKs; Project 3; Leader, Hammerman and co-Leader, Meyerson) using a focused medicinal chemistry approach. Through collaborations with the three Projects, the Structure Core (Director, Eck), and the Animal Core (Director, Wong), the Chemistry Core will perform medicinal chemistry to develop and optimize inhibitors?to be used alone or as ?selective degraders??that exhibit the potency, selectivity, and pharmacological properties sufficient to enable their use in the proposed cellular and in vivo studies.
Lung cancer is a devastating disease in desperate need for better treatment options. Recent breakthroughs have come from a new class of drugs that target key enzymes that become hyper activated in lung tumors. Unfortunately the lung tumors become resistant to these drugs and new strategies are needed. In this proposal we are developing a new class of drugs that induce the degradation rather than the direct inhibition of these key enzymes, in collaboration with all three Research Projects and the other Resource Cores. We believe this new strategy of protein degradation may represent a superior approach to treating lung cancer.
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