HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential...

Area of Science:

• Oncology
• Medicinal Chemistry
• Molecular Biology

Background:

• Heat Shock Factor 1 (HSF1) is a transcription factor implicated in cancer malignancy.
• Developing targeted therapies for refractory ovarian cancer remains a critical unmet need.

Purpose of the Study:

• To optimize a chemical probe (CCT251236) targeting HSF1 transcription into a clinical candidate.
• To develop potent and orally bioavailable inhibitors of HSF1 for cancer treatment.

Main Methods:

• Utilized cell-based phenotypic high-throughput screening (HTS) to identify HSF1 inhibitors.
• Employed matched molecular pair analysis to address P-glycoprotein efflux liabilities.
• Conducted multiparameter optimization to design the clinical candidate CCT361814/NXP800.

Main Results:

• CCT251236 was identified as a potent HSF1 inhibitor.
• Central ring halogen substitution effectively reduced P-glycoprotein efflux.
• CCT361814/NXP800 demonstrated tumor regression in ovarian cancer xenografts with biomarker modulation and favorable safety.

Conclusions:

• CCT361814/NXP800 is a potent, orally bioavailable HSF1 inhibitor with potential for treating refractory ovarian cancer.
• The compound has advanced to phase 1 clinical trials.
• This work highlights a successful drug development pathway from HTS to clinical candidate for HSF1-mediated malignancies.