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Your search keyword '"Waters LM"' showing total 2 results
Start Over Author "Waters LM" Topic phthalazines
2 results on '"Waters LM"'

1. Design and evaluation of achiral, non-atropisomeric 4-(aminomethyl)phthalazin-1(2H)-one derivatives as novel PRMT5/MTA inhibitors.

Author

Smith CR, Aranda R, Christensen JG, Engstrom LD, Gunn RJ, Ivetac A, Ketcham JM, Kuehler J, David Lawson J, Marx MA, Olson P, Thomas NC, Wang X, Waters LM, and Kulyk S

Subjects
Humans, Crystallography, X-Ray, Protein-Arginine N-Methyltransferases, Enzyme Inhibitors pharmacology, Neoplasms drug therapy, Phthalazines pharmacology
Abstract

MRTX1719 is an inhibitor of the PRMT5/MTA complex and recently entered clinical trials for the treatment of MTAP-deleted cancers. MRTX1719 is a class 3 atropisomeric compound that requires a chiral synthesis or a chiral separation step in its preparation. Here, we report the SAR and medicinal chemistry design strategy, supported by structural insights from X-ray crystallography, to discover a class 1 atropisomeric compound from the same series that does not require a chiral synthesis or a chiral separation step in its preparation., (Copyright © 2022 Mirati Therapeutics, Inc. Published by Elsevier Ltd.. All rights reserved.)

Published
2022
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2. Fragment-Based Discovery of MRTX1719, a Synthetic Lethal Inhibitor of the PRMT5•MTA Complex for the Treatment of MTAP -Deleted Cancers.

Author

Smith CR, Aranda R, Bobinski TP, Briere DM, Burns AC, Christensen JG, Clarine J, Engstrom LD, Gunn RJ, Ivetac A, Jean-Baptiste R, Ketcham JM, Kobayashi M, Kuehler J, Kulyk S, Lawson JD, Moya K, Olson P, Rahbaek L, Thomas NC, Wang X, Waters LM, and Marx MA

Subjects
Animals, Antineoplastic Agents chemical synthesis, Antineoplastic Agents metabolism, Cell Line, Tumor, Deoxyadenosines metabolism, Female, Gene Deletion, Humans, Mice, Nude, Phthalazines chemical synthesis, Phthalazines metabolism, Protein Binding, Protein-Arginine N-Methyltransferases metabolism, Purine-Nucleoside Phosphorylase deficiency, Purine-Nucleoside Phosphorylase genetics, Thionucleosides metabolism, Xenograft Model Antitumor Assays, Mice, Antineoplastic Agents therapeutic use, Neoplasms drug therapy, Phthalazines therapeutic use, Protein-Arginine N-Methyltransferases antagonists & inhibitors
Abstract

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP -deleted cancers. Here, we report the discovery of development candidate MRTX1719 . MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP -deleted cells compared to MTAP -wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP -deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2 H )-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719 .

Published
2022
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