Andrew Germain
Broad Institute
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Featured researches published by Andrew Germain.
Bioorganic & Medicinal Chemistry Letters | 2012
Andrew Germain; Leigh C. Carmody; Barbara Morgan; Cristina Fernandez; Erin Forbeck; Tim Lewis; Partha Nag; Amal Ting; Lynn VerPlank; Yuxiong Feng; Jose R. Perez; Sivaraman Dandapani; Michelle Palmer; Eric S. Lander; Piyush B. Gupta; Stuart L. Schreiber; Benito Munoz
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).
Journal of Biomolecular Screening | 2012
Leigh C. Carmody; Andrew Germain; Lynn VerPlank; Partha Nag; Benito Munoz; Jose R. Perez; Michelle Palmer
Cancer stem cells (CSCs) are resistant to standard cancer treatments and are likely responsible for cancer recurrence, but few therapies target this subpopulation. Due to the difficulty in propagating CSCs outside of the tumor environment, previous work identified CSC-like cells by inducing human breast epithelial cells into an epithelial-to-mesenchymal transdifferentiated state (HMLE_sh_ECad). A phenotypic screen was conducted against HMLE_sh_ECad with 300 718 compounds from the Molecular Libraries Small Molecule Repository to identify selective inhibitors of CSC growth. The screen yielded 2244 hits that were evaluated for toxicity and selectivity toward an isogenic control cell line. An acyl hydrazone scaffold emerged as a potent and selective scaffold targeting HMLE_sh_ECad. Fifty-three analogues were acquired and tested; compounds ranged in potency from 790 nM to inactive against HMLE_sh_ECad. Of the analogues, ML239 was best-in-class with an IC50= 1.18 µM against HMLE_sh_ECad, demonstrated a >23-fold selectivity over the control line, and was toxic to another CSC-like line, HMLE_shTwist, and a breast carcinoma cell line, MDA-MB-231. Gene expression studies conducted with ML239-treated cells showed altered gene expression in the NF-κB pathway in the HMLE_sh_ECad line but not in the isogenic control line. Future studies will be directed toward the identification of ML239 target(s).
ACS Medicinal Chemistry Letters | 2014
Sivaraman Dandapani; Andrew Germain; Ivan Jewett; Sebastian le Quement; Jean-Charles Marie; Giovanni Muncipinto; Jeremy R. Duvall; Leigh C. Carmody; Jose R. Perez; Juan C. Engel; Jiri Gut; Danielle Kellar; Jair L. Siqueira-Neto; James H. McKerrow; Marcel Kaiser; Ana Rodriguez; Michelle Palmer; Michael Foley; Stuart L. Schreiber; Benito Munoz
A phenotypic high-throughput screen using ∼100,000 compounds prepared using Diversity-Oriented Synthesis yielded stereoisomeric compounds with nanomolar growth-inhibition activity against the parasite Trypanosoma cruzi, the etiological agent of Chagas disease. After evaluating stereochemical dependence on solubility, plasma protein binding and microsomal stability, the SSS analogue (5) was chosen for structure-activity relationship studies. The p-phenoxy benzyl group appended to the secondary amine could be replaced with halobenzyl groups without loss in potency. The exocyclic primary alcohol is not needed for activity but the isonicotinamide substructure is required for activity. Most importantly, these compounds are trypanocidal and hence are attractive as drug leads for both acute and chronic stages of Chagas disease. Analogue (5) was nominated as the molecular libraries probe ML341 and is available through the Molecular Libraries Probe Production Centers Network.
Bioorganic & Medicinal Chemistry Letters | 2013
Andrew Germain; Leigh C. Carmody; Partha Nag; Barbara Morgan; Lynn VerPlank; Cristina Fernandez; Etienne J. Donckele; Yuxiong Feng; Jose R. Perez; Sivaraman Dandapani; Michelle Palmer; Eric S. Lander; Piyush B. Gupta; Stuart L. Schreiber; Benito Munoz
A high-throughput screen (HTS) was conducted against stably propagated cancer stem cell (CSC)-enriched populations using a library of 300,718 compounds from the National Institutes of Health (NIH) Molecular Libraries Small Molecule Repository (MLSMR). A cinnamide analog displayed greater than 20-fold selective inhibition of the breast CSC-like cell line (HMLE_sh_Ecad) over the isogenic control cell line (HMLE_sh_eGFP). Herein, we report structure-activity relationships of this class of cinnamides for selective lethality towards CSC-enriched populations.
Bioorganic & Medicinal Chemistry Letters | 2011
Andrew Germain; Leigh C. Carmody; Chris Dockendorff; Cristina Galan-Rodriguez; Ana Rodriguez; Stephen Johnston; Joshua Bittker; Lawrence MacPherson; Sivaraman Dandapani; Michelle Palmer; Stuart L. Schreiber; Benito Munoz
We report the outcome of a high-throughput small-molecule screen to identify novel, nontoxic, inhibitors of Trypansoma cruzi, as potential starting points for therapeutics to treat for both the acute and chronic stages of Chagas disease. Two compounds were identified that displayed nanomolar inhibition of T. cruzi and an absence of activity against host cells at the highest tested dose. These compounds have been registered with NIH Molecular Libraries Program (probes ML157 and ML158).
ACS Chemical Biology | 2016
Florence F. Wagner; Joshua A. Bishop; Jennifer Gale; Xi Shi; Michelle Walk; Joshua Ketterman; Debasis Patnaik; Doug Barker; Deepika Walpita; Arthur J. Campbell; Shannon Nguyen; Michael C. Lewis; Linda Ross; Michel Weiwer; W. Frank An; Andrew Germain; Partha Nag; Shailesh R Metkar; Taner Kaya; Sivaraman Dandapani; David E. Olson; Anne-Laure Barbe; Fanny Lazzaro; Joshua R. Sacher; Jaime H. Cheah; David Fei; Jose R. Perez; Benito Munoz; Michelle Palmer; Kimberly Stegmaier
The mood stabilizer lithium, the first-line treatment for bipolar disorder, is hypothesized to exert its effects through direct inhibition of glycogen synthase kinase 3 (GSK3) and indirectly by increasing GSK3s inhibitory serine phosphorylation. GSK3 comprises two highly similar paralogs, GSK3α and GSK3β, which are key regulatory kinases in the canonical Wnt pathway. GSK3 stands as a nodal target within this pathway and is an attractive therapeutic target for multiple indications. Despite being an active field of research for the past 20 years, many GSK3 inhibitors demonstrate either poor to moderate selectivity versus the broader human kinome or physicochemical properties unsuitable for use in in vitro systems or in vivo models. A nonconventional analysis of data from a GSK3β inhibitor high-throughput screening campaign, which excluded known GSK3 inhibitor chemotypes, led to the discovery of a novel pyrazolo-tetrahydroquinolinone scaffold with unparalleled kinome-wide selectivity for the GSK3 kinases. Taking advantage of an uncommon tridentate interaction with the hinge region of GSK3, we developed highly selective and potent GSK3 inhibitors, BRD1652 and BRD0209, which demonstrated in vivo efficacy in a dopaminergic signaling paradigm modeling mood-related disorders. These new chemical probes open the way for exclusive analyses of the function of GSK3 kinases in multiple signaling pathways involved in many prevalent disorders.
Bioorganic & Medicinal Chemistry Letters | 2015
Chris Dockendorff; Patrick W. Faloon; Andrew Germain; Miao Yu; Willmen Youngsaye; Partha Nag; Melissa Bennion; Marsha Penman; Thomas J.F. Nieland; Sivaraman Dandapani; Jose R. Perez; Benito Munoz; Michelle Palmer; Stuart L. Schreiber; Monty Krieger
A new series of potent inhibitors of cellular lipid uptake from HDL particles mediated by scavenger receptor, class B, type I (SR-BI) was identified. The series was identified via a high-throughput screen of the National Institutes of Health Molecular Libraries Small Molecule Repository (NIH MLSMR) that measured the transfer of the fluorescent lipid DiI from HDL particles to CHO cells overexpressing SR-BI. The series is characterized by a linear peptidomimetic scaffold with two adjacent amide groups, as well as an aryl-substituted heterocycle. Analogs of the initial hit were rapidly prepared via Ugi 4-component reaction, and select enantiopure compounds were prepared via a stepwise sequence. Structure-activity relationship (SAR) studies suggest an oxygenated arene is preferred at the western end of the molecule, as well as highly lipophilic substituents on the central and eastern nitrogens. Compound 5e, with (R)-stereochemistry at the central carbon, was designated as probe ML279. Mechanistic studies indicate that ML279 stabilizes the interaction of HDL particles with SR-BI, and its effect is reversible. It shows good potency (IC50=17 nM), is non-toxic, plasma stable, and has improved solubility over our alternative probe ML278.
ACS Medicinal Chemistry Letters | 2012
Chris Dockendorff; Marek M. Nagiec; Michel Weiwer; Sara J. Buhrlage; Amal Ting; Partha Nag; Andrew Germain; Han-Je Kim; Willmen Youngsaye; Christina Scherer; Melissa Bennion; Linlong Xue; BenjaminZ. Stanton; Tim Lewis; Lawrence MacPherson; Michelle Palmer; Michael A. Foley; Jose R. Perez; Stuart L. Schreiber
Archive | 2014
W. Frank An; Andrew Germain; Joshua A. Bishop; Partha Nag; Shailesh R Metkar; Joshua Ketterman; Michelle Walk; Michel Weiwer; Xiulin Liu; Debasis Patnaik; Yan-Ling Zhang; Jennifer Gale; Wendy Zhao; Taner Kaya; Doug Barker; Florence F. Wagner; Ed B. Holson; Sivaraman Dandapani; José Luis Gutiérrez Pérez; Benito Munoz; Michelle Palmer; Jen Q. Pan; Stephen J. Haggarty; Stuart L Schreiber
Archive | 2013
Leigh C. Carmody; Andrew Germain; Juan C. Engel; Jiri Gut; Marcel Kaiser; Ivan Jewett; Sebastian LeQuemen; Jean-Charles Marie; Sivaraman Dandapani; Ana Rodriguez; Jose R. Perez; James H. McKerrow; Michelle Palmer; Benito Munoz; Stuart L. Schrieber