Charles F. McHugh

Asymmetric synthesis of potent and orally bioavailable thiophene-based EZH2 inhibitors

Xinrong Tian, K. A. NEWLANDER, Louis V. LaFrance, James F. Mack et autres

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Abstract 4854: Alleviation of low pH induced immunosuppression through antagonism of the pH sensor GPR65 in highly glycolytic NSCLC tumors

Prajna Behera, Samantha N. Buongervino, Kayla Guidry, Kyle Krois et autres

Abstract Out of more than 5683 clinical trials testing anti-PD1/PDL1 mAbs, on average only 20% of patients achieved an objective response, leaving an unmet need for patients who do not respond to immune checkpoint inhibitors (ICIs)(Zhao et al, 2020, Upadhyaya et al, …

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Discovery of Potent STT3A/B Inhibitors and Assessment of Their Multipathogen Antiviral Potential and Safety

Joseph E. Pero, Elizabeth A. Mueller, Ashley M. Adams, Ramona S. Adolph et autres

In the aftermath of the COVID-19 pandemic, opportunities to modulate biological pathways common to the lifecycles of viruses need to be carefully considered. N -linked glycosylation in humans is mediated exclusively by the oligosaccharyltransferase complex and is frequently hijacked by viruses to …

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N-Nitrosodimethylamine investigations in Muta™Mouse define point-of-departure values and demonstrate less-than-additive somatic mutant frequency accumulations

Anthony M Lynch, Jonathan Howe, Deon Hildebrand, James Harvey et autres

The N-nitrosamine, N-nitrosodimethylamine (NDMA), is an environmental mutagen and rodent carcinogen. Small levels of NDMA have been identified as an impurity in some commonly used drugs, resulting in several product recalls. In this study, NDMA was evaluated in an OECD TG-488 compliant …

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Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells

Christina N. Di Marco, Lamont R. Terrell, Robert A. Sanchez, Lourdes Rueda et autres

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Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening

Dominic Suarez, Douglas W. Thomson, William Li, Elizabeth A. King et autres

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been …

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Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c -MYC Protein Levels in Cells

Jesús R. Medina, Xinrong Tian, William Li, Dominic Suarez et autres

Elevated expression of the c -MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small …

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Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia

Melissa B. Pappalardi, Kathryn Keenan, Mark Cockerill, Wendy A. Kellner et autres

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Identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition in blood and tumor tissues

Paul Noto, Timothy W. Sikorski, Francesca Zappacosta, Craig D. Wagner et autres

Arginine methylation has been recognized as a post-translational modification with pleiotropic effects that span from regulation of transcription to metabolic processes that contribute to aberrant cell proliferation and tumorigenesis. This has brought significant attention to the development of therapeutic strategies aimed at …

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Discovery of Isoxazole Amides as Potent and Selective SMYD3 Inhibitors

Dai‐Shi Su, Junya Qu, Mark J. Schulz, Chuck W. Blackledge et autres

We report herein the discovery of isoxazole amides as potent and selective SET and MYND Domain-Containing Protein 3 (SMYD3) inhibitors. Elucidation of the structure–activity relationship of the high-throughput screening (HTS) lead compound 1 provided potent and selective SMYD3 inhibitors. The SAR optimization, …

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Anti-tumor Activity of the Type I PRMT Inhibitor, GSK3368715, Synergizes with PRMT5 Inhibition through MTAP Loss

Andrew Fedoriw, Satyajit Rajapurkar, Shane W. O’Brien, Sarah V. Gerhart et autres

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Abstract 2994: Discovery of selective, noncovalent small molecule inhibitors of DNMT1 as an alternative to traditional DNA hypomethylating agents

Melissa B. Pappalardi, Mark Cockerill, Jessica L. Handler, Alexandra Stowell et autres

Abstract Aberrant DNA hypermethylation within promoter regions and subsequent gene silencing are near universal hallmarks of human cancer. Reversal of DNA methylation by a hypomethylating agent, such as decitabine (Dacogen) or azacytidine (Vidaza), has shown clinical benefit for the treatment of heme …

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