HSF1 Pathway Inhibitor Clinical Candidate (CCT361814/NXP800) Developed from a Phenotypic Screen as a Potential Treatment for Refractory Ovarian Cancer and Other Malignancies.
Embargo End Date
ICR Authors
Authors
Pasqua, AE
Sharp, SY
Chessum, NEA
Hayes, A
Pellegrino, L
Tucker, MJ
Miah, A
Wilding, B
Evans, LE
Rye, CS
Mok, NY
Liu, M
Henley, AT
Gowan, S
De Billy, E
Te Poele, R
Powers, M
Eccles, SA
Clarke, PA
Raynaud, FI
Workman, P
Jones, K
Cheeseman, MD
Sharp, SY
Chessum, NEA
Hayes, A
Pellegrino, L
Tucker, MJ
Miah, A
Wilding, B
Evans, LE
Rye, CS
Mok, NY
Liu, M
Henley, AT
Gowan, S
De Billy, E
Te Poele, R
Powers, M
Eccles, SA
Clarke, PA
Raynaud, FI
Workman, P
Jones, K
Cheeseman, MD
Document Type
Journal Article
Date
2023-04-27
Date Accepted
2023-04-27
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.
Citation
Journal of Medicinal Chemistry, 2023, 66 (8), pp. 5907 - 5936
Source Title
Journal of Medicinal Chemistry
Publisher
AMER CHEMICAL SOC
ISSN
0022-2623
eISSN
1520-4804
1520-4804
1520-4804
Collections
Research Team
RNA Bio & Mol Therap
Clinical Pharma & Trials
Signal Trans & Mol Pharma
Medicinal Chemistry 3
Clinical Pharma & Trials
Signal Trans & Mol Pharma
Medicinal Chemistry 3