Hendrik Luesch, Ph.D.

Hendrik Luesch, Ph.D., a professor of medicinal chemistry, received his Diplom in Chemistry at the University of Siegen (Germany) in 1997. He studied marine natural products chemistry at the University of Hawaii at Manoa and obtained his Ph.D. with Professor Richard E. Moore in 2002. He undertook three years of postdoctoral studies as an Irving S. Sigal Fellow at The Scripps Research Institute with Professor Peter G. Schultz in functional genomics and chemical biology. In 2005 he joined the faculty of the Department of Medicinal Chemistry at the University of Florida (UF) as an assistant professor and was tenured and promoted to associate professor in 2010 and to full professor in 2015. He holds the endowed Debbie and Sylvia DeSantis Chair in Natural Products Drug Discovery and Development and serves as Department Chair. He leads a multidisciplinary marine natural products program with chemistry- and genomics-based discovery platforms that integrate classical isolation and spectroscopic structure determination, genome mining and synthetic biology, chemical synthesis, target identification, and mechanism of action as well as early development studies. He is founding Director of UF’s Center for Natural Products, Drug Discovery and Development (CNPD3). He has published over 180 papers, is inventor on 40 issued patents (US, PCT and nationalized) and cofounded several companies. He has received the UF Technology Innovator Award for several years and the UF 2021 Innovation of the Year award.

Dr. Luesch‘s multidisciplinary research program at the interface of chemistry and biology integrates genome mining, synthetic and chemical biology, isolation and spectroscopic structure determination, chemical synthesis, target identification and mechanism of action studies, followed by the preclinical development of candidate molecules. Under the CNPD3 umbrella, he is leading a collaborative “Genomes to Natural Products to Drugs” initiative. His lab is producing a small but increasing pipeline of bioactive compounds that are at various developmental stages.

His lab has been working closely with chemical ecologist Valerie Paul, Ph.D. (Smithsonian Marine Station) and discovered numerous novel bioactive compounds from marine sources, particularly cyanobacteria, as starting points for drug discovery and development. He discovered the potent microtubule-destabilizer dolastatin 10 from a marine cyanobacterium. Dolastatin 10 has provided the basis for six marketed anticancer drugs to date. Antibody-drug conjugates (ADCs) of the dolastatin 10 analogue MMAE have been FDA approved for Hodgkin’s lymphoma and anaplastic large cell lymphoma (brentuximab vedotin), B-cell lymphoma (polatuzumab vedotin), refractory bladder cancer (enfortumab vedotin), relapsed/refractory multiple myeloma (belantamab mafodotin), various breast, gastric and urothelial cancers (disitamab vedotin), and metastatic cervical cancer (tisotumab vedotin).

His team discovered a new chemical scaffold from marine cyanobacteria, gatorbulin-1, that targets a new tubulin pharmacological site. They reported the entire spectrum of the discovered chemical and biological novelties, including the isolation, structure determination, chemical synthesis, mechanism of action, target identification, and binding mode elucidation at the atomic level. His team discovered, synthesized and performed the in vitro and in vivo evaluation as well as preclinical developmental studies for largazole, one of the most potent class I histone deacetylase (HDAC) inhibitors. He discovered apratoxins and subsequently characterized the novel mechanism of action through genomic and proteomic approaches, revealing that this class of natural products inhibits cotranslational translocation in the secretory pathway. Medicinal chemistry efforts paved the way for the development of synthetic apratoxins for pancreatic and colon cancer, retinal angiogenic diseases, and as broad-spectrum antivirals. His team also discovered, synthesized and tuned selectivity profiles of protease inhibitors, GPCR modulators, cytoskeletal and cell membrane targeting agents, as well as many other natural products with various functions. In general, his team puts significant biology behind all discoveries to enhance the value of the natural products and to enable the best chances for development. He and his team discovered approximately 200 natural products belonging to over 50 chemical scaffolds and have started to identify biosynthetic gene clusters from metagenomes and translating them (or key building blocks) into chemicals to address supply issues through heterologous production or a hybrid synthetic biology/chemistry approach (e.g., apratoxins).

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