Discovery of 4,6-disubstituted Pyrimidines As Potent Inhibitors of the Heat Shock Factor 1 (HSF1) Stress Pathway and CDK9

Overview

Journal Medchemcomm

Publisher Royal Society of Chemistry

Specialty Chemistry

Date 2016 Oct 18

PMID 27746890

Citations 11

Authors

Carl S Rye

Nicola E A Chessum

Scott Lamont

Kurt G Pike

Paul Faulder

Julie Demeritt

Paul Kemmitt

Julie Tucker

Lorenzo Zani

Matthew D Cheeseman

Rosie Isaac

Louise Goodwin

Joanna Boros

Florence Raynaud

Angela Hayes

Alan T Henley

Emmanuel de Billy

Christopher J Lynch

Swee Y Sharp

Robert Te Poele

Lisa O Fee

Kevin M Foote

Stephen Green

Paul Workman

Keith Jones

Affiliations

Soon will be listed here.

Abstract

Heat shock factor 1 (HSF1) is a transcription factor that plays key roles in cancer, including providing a mechanism for cell survival under proteotoxic stress. Therefore, inhibition of the HSF1-stress pathway represents an exciting new opportunity in cancer treatment. We employed an unbiased phenotypic screen to discover inhibitors of the HSF1-stress pathway. Using this approach we identified an initial hit () based on a 4,6-pyrimidine scaffold (2.00 μM). Optimisation of cellular SAR led to an inhibitor with improved potency (, 15 nM) in the HSF1 phenotypic assay. The 4,6-pyrimidine was also shown to have high potency against the CDK9 enzyme (3 nM).

Citing Articles

Heat Shock Factor 1 Inhibition: A Novel Anti-Cancer Strategy with Promise for Precision Oncology.

Gumilar K, Chin Y, Ibrahim I, Tjokroprawiro B, Yang J, Zhou M Cancers (Basel). 2023; 15(21).

PMID: 37958341 PMC: 10649344. DOI: 10.3390/cancers15215167.

Targeting HSF1 for cancer treatment: mechanisms and inhibitor development.

Chin Y, Gumilar K, Li X, Tjokroprawiro B, Lu C, Lu J Theranostics. 2023; 13(7):2281-2300.

PMID: 37153737 PMC: 10157728. DOI: 10.7150/thno.82431.

HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies.

Pasqua A, Sharp S, Chessum N, Hayes A, Pellegrino L, Tucker M J Med Chem. 2023; 66(8):5907-5936.

PMID: 37017629 PMC: 10150365. DOI: 10.1021/acs.jmedchem.3c00156.

Orally bioavailable CDK9/2 inhibitor shows mechanism-based therapeutic potential in MYCN-driven neuroblastoma.

Poon E, Liang T, Jamin Y, Walz S, Kwok C, Hakkert A J Clin Invest. 2020; 130(11):5875-5892.

PMID: 33016930 PMC: 7598076. DOI: 10.1172/JCI134132.

The Multifaceted Role of HSF1 in Tumorigenesis.

Alasady M, Mendillo M Adv Exp Med Biol. 2020; 1243:69-85.

PMID: 32297212 PMC: 8236212. DOI: 10.1007/978-3-030-40204-4_5.

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