Medicinal Chemistry and Mode-of-Action

As part of an extensive medicinal chemistry program in collaboration with Beatriz Fontoura (Cell Biology) and Meg Phillips (Pharmacology), we synthesized the most potent DHODH-inhibitor reported to date (IC50 1 nM) that inhibited viral replication of VSV and WSN-Influenza (EC50 2 nM and 41 nM), and solved the X-ray structure of human DHODH bound to this potent novel inhibitor.

X-ray structure of human DHODH bound to a novel inhibitor – ACS Med. Chem. Lett. 2013, 4, 517
X-ray structure of human DHODH bound to a novel inhibitor – ACS Med. Chem. Lett. 2013, 4, 517

In collaboration with Meg Phillips, we are also engaged in a medicinal chemistry program to identify small molecule inhibitors of the trypanosomal S-adenosylmethionine decarboxylase (AdoMetDC) for the treatment of Human African Trypanosomiasis (African sleeping sickness).

In collaboration with Luis Parada (MSKCC), we developed several different novel small molecule collections from four different scaffolds with different modes-of-action that potently (0.5-10 nM) and selectively kill tumor-derived neuronal stem cells for the potential treatment of glioblastoma. One series was found to specifically inhibit oxidative phosphorylation via inhibition of complex I of the respiratory chain (via biotinylated pull-down), and another series was found to inhibit late-stage cholesterol biosynthesis. Mode-of-action studies of the two remaining series are ongoing (in collaboration with Deepak Nijhawan). 

In a collaboration with Jerry Shay (Cell Biology) aimed at identifying compounds with selectivity for colon cancer cells with truncating mutations in the APC gene, we initiated a medicinal chemistry program that led to an analog collection of piperidinyl sulfonamides (>200) that kill truncating APC-expressing colon cancers with exquisite in vitro selectivity versus any other cell lines that lack these mutations (picomolar versus 10 µM!). This selectivity was maintained in vivo (xenografts) and a non-toxic orally available analog successfully prevented the development of colon cancer in a GEM mouse model of familial adenomatous polyposis.

Other collaborative synthetic and medicinal chemistry-oriented projects in our lab include structure-based design of orexin-receptor agonists for narcolepsy (with Dan Rosenbaum) and development of novel natural product-based antibiotics for Gram-negative infections (with John MacMillan).