Room 209 Havemeyer, 3000 Broadway, New York, NY 10027
Presented by Petr Vachal, Merck & Co., Inc.
The Invention of MK-8262, a CETP Inhibitor for the Treatment of Coronary Heart Disease Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles including the HDL and the LDL particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction which is consistent with clinical outcome trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction as compared to standard of care alone. We discuss the invention of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.
Petr Vachal is an accomplished drug hunter and an executive manager with a track record of success, building successful teams and providing scientific leadership, working across therapeutically important areas, diverse modalities and enabling technologies, spanning from target & lead discovery to clinical candidate nomination and early clinical development. Petr is currently AVP Chemistry, Head of the NJ Discovery, Global Head of External Discovery Chemistry, Sample Management and Operations at Merck & Co (MSD). Petr is responsible for global drug discovery pipeline across all disease areas (cardiovascular, oncology, immuno- oncology, neuroscience, infectious diseases), capabilities (medicinal chemistry, HT-E, automation, engineering), and modalities (small molecules, peptides, oligos, degraders); accountable for hit-to-lead-to-clinical candidate deliverables. Prior responsibilities included creation and leadership of Screening, Target & Compound Profiling (STCP), an organization globally responsible for portfolio of screening platforms, chemical biology, biophysics, protein biochemistry, external sourcing partnerships, compound management and operations, as well as inception and leadership of Automation & Capabilities Enhancement (ACE), an organization dramatically accelerating discovery chemistry pipeline through development and application of enabling capabilities (first to develop the concept of high-throughput experimentation, late-stage functionalization, and micro purification). Under Petr’s leadership, the success rate for finding viable leads for all prioritized targets in the portfolio has increased dramatically (95% success rate), several new targets have been identified from a portfolio of disease-relevant phenotypes, and & 20 candidates were delivered into the clinic (10 of these candidates are currently progressing through Ph1-2 clinical trials). Petr received Ph.D. from Harvard University (graduate advisor Eric N. Jacobsen).
Presented by Todd Hyster, Cornell University
Enzymes are exquisite catalysts for chemical synthesis, capable of providing unparalleled levels of chemo-, regio-, diastereo- and enantioselectivity. Unfortunately, biocatalysts are often limited to the reactivity patterns found in nature. In this talk, I will share my groups efforts to use light to expand the reactivity profile of enzymes. In our studies, we have exploited the photoexcited state of common biological cofactors, such as NADH and FMN to facilitate electron transfer to substrates bound within enzyme active sites. In other studies, we found that enzymes will electronically activate bound substrates for electron transfer. In the presence of common photoredox catalysts, this activation can be used to direct radical formation to enzyme active sites. Using these approaches, we are able to develop biocatalysts to solve long-standing selectivity challenges in chemical synthesis.