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

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.