Publications (4)6.01 Total impact
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Article: Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies.
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ABSTRACT: Macrocyclic Hedgehog (Hh) pathway inhibitors have been discovered with improved potency and maximal inhibition relative to the previously reported macrocycle robotnikinin. Analogues were prepared using a modular and efficient build-couple-pair (BCP) approach, with a ring-closing metathesis step to form the macrocyclic ring. Varying the position of the macrocycle nitrogen and oxygen atoms provided inhibitors with improved activity in cellular assays; the most potent analogue was 29 (BRD-6851), with an IC(50) of 0.4 μM against C3H10T1/2 cells undergoing Hh-induced activation, as measured by Gli1 transcription and alkaline phosphatase induction. Studies with Patched knockout (Ptch(-/-)) cells and competition studies with the Smoothened (Smo) agonists SAG and purmorphamine demonstrate that in contrast to robotnikinin, select analogues are Smo antagonists.ACS Medicinal Chemistry Letters 10/2012; 3(10):808-813. · 3.36 Impact Factor -
Article: Identification of a selective small molecule inhibitor of breast cancer stem cells.
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ABSTRACT: A high-throughput screen (HTS) with the National Institute of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR) compound collection identified a class of acyl hydrazones to be selectively lethal to breast cancer stem cell (CSC) enriched populations. Medicinal chemistry efforts were undertaken to optimize potency and selectivity of this class of compounds. The optimized compound was declared as a probe (ML239) with the NIH Molecular Libraries Program and displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control line (HMLE_sh_GFP).Bioorganic & medicinal chemistry letters 01/2012; 22(10):3571-4. · 2.65 Impact Factor -
Chapter: Identification of Small Molecule Inhibitors that Suppress Cytokine-Induced Apoptosis in Human Pancreatic Islet Cells
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ABSTRACT: Type 1 diabetes is caused by autoimmune destruction of insulin-producing beta cells in the pancreas. In this process, beta-cell apoptosis involves multiple signaling cascades stimulated by interleukin-1β (IL-1β), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α). These pathways result in decreased pancreatic beta-cell numbers that lead to the disease phenotype. Most of the compounds described in the literature protect cells from a single facet of cytokine treatment but do not provide wide-ranging protection from apoptosis nor do they restore insulin secretion. The goal of this project was to identify and to optimize small molecules that can prevent cytokine-induced pancreatic beta-cell apoptosis. To achieve this goal, we completed a screen of 339,000 compounds in rat INS-1E insulinoma cells treated with IL-1β, IFN-γ, and TNF-α. As a result, we identified MLS003179189, a member of a novel diversity-oriented synthesis (DOS) library with stereochemical diversity and complexity akin to naturally occurring small molecules. MLS003179189 contains 3 stereocenters and was the only stereoisomer (out of eight possible stereoisomers) to show activity in the primary assay for cell viability. About 50 analogs of the active stereoisomer were synthesized and tested, leading to a superior probe candidate (ML187). In studies with dissociated human primary pancreatic islets, (ML187) improved cell viability, decreased caspase activation, and improved insulin production. These data suggest that a consistent mechanism of action exists in both rat and human cells and that the probe (ML187) is a first-in-class probe for Type I diabetes that both protects against destruction of beta cells and restores function. -
Chapter: Identification of small molecules that selectively inhibit fluconazole-resistant Candida albicans in the presence of fluconazole but not in its absence - Probe 2
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ABSTRACT: The effectiveness of the potent antifungal drug fluconazole has been compromised by the rise of drug-resistant fungal pathogens. It has been observed that inhibition of Hsp90 can reverse drug resistance in Candida; however, it is challenging to find fungal-specific inhibitors of Hsp90 that do not also impair the human host protein. The Molecular Libraries Probe Production Centers Network (MLPCN) library was screened in duplicate dosings to identify compounds that selectively reverse fluconazole resistance in a Candida albicans clinical isolate, while having no antifungal activity when administered as a single agent. An indazole compound (CID3243873) was identified as meeting most of the probe criteria, and subsequent SAR identified a more potent analog as a new probe compound (ML212).
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2012
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Broad Institute of MIT and Harvard
Cambridge, MA, USA
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