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

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

  • J Med Chem. 2023 Apr 5. doi: 10.1021/acs.jmedchem.3c00156.
A Elisa Pasqua 1,  Swee Y Sharp 1,  Nicola E A Chessum 1,  Angela Hayes 1,  Loredana Pellegrino 1,  Michael J Tucker 1,  Asadh Miah 1,  Birgit Wilding 1,  Lindsay E Evans 1,  Carl S Rye 1,  N Yi Mok 1,  Manjuan Liu 1,  Alan T Henley 1,  Sharon Gowan 1,  Emmanuel De Billy 1,  Robert Te Poele 1,  Marissa Powers 1,  Suzanne A Eccles 1,  Paul A Clarke 1,  Florence I Raynaud 1,  Paul Workman 1,  Keith Jones 1,  Matthew D Cheeseman 1
Affiliations

Affiliation

  • 1 Centre for Cancer Drug Discovery and Division of Cancer Therapeutics at The Institute of Cancer Research, London SW7 3RP, United Kingdom.
PMID: 37017629 DOI: 10.1021/acs.jmedchem.3c00156
Abstract

CCT251236 1, a potent chemical probe, was previously developed from a cell-based phenotypic high-throughput screen (HTS) to discover inhibitors of transcription mediated by HSF1, a transcription factor that supports malignancy. Owing to its activity against models of refractory human ovarian Cancer, 1 was progressed into lead optimization. The reduction of P-glycoprotein efflux became a focus of early compound optimization; central ring halogen substitution was demonstrated by matched molecular pair analysis to be an effective strategy to mitigate this liability. Further multiparameter optimization led to the design of the clinical candidate, CCT361814/NXP800 22, a potent and orally bioavailable fluorobisamide, which caused tumor regression in a human ovarian adenocarcinoma xenograft model with on-pathway biomarker modulation and a clean in vitro safety profile. Following its favorable dose prediction to human, 22 has now progressed to phase 1 clinical trial as a potential future treatment for refractory ovarian Cancer and other malignancies.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145927
    99.79%, HSF1 pathway Inhibitor
    HSP