Author: Huang, Zhao ; Tang, Yongquan ; Chen, Zhe-Sheng ; Zhang, Jian ; Nice, Edouard C ; Li, Bowen ; Shao, Jichun ; Luo, Yinheng ; Zhou, Li ; Lu, Yi ; Xie, Na ; Zhang, Zhe ; Weng, Ningna ; Jiang, Jingwen ; Qin, Siyuan ; Huang, Canhua

It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.

01 Dec 2015·Nature Chemical BiologyQ1 · BIOLOGY

A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease

Q1 · BIOLOGY

Article

Author: Stubbs, Mark ; Fraser, Elizabeth ; Ewan, Ken ; Blaukat, Andree ; Rohdich, Felix ; Gowan, Sharon ; Clarke, Paul A ; Workman, Paul ; Adeniji-Popoola, Olajumoke ; Raynaud, Florence ; Valenti, Melanie ; Musil, Djordje ; Wienke, Dirk ; Poeschke, Oliver ; Blagg, Julian ; Court, Will ; Dale, Trevor ; Box, Gary ; Esdar, Christina ; Ortiz-Ruiz, Maria-Jesus ; Eccles, Suzanne A ; Samant, Rahul S ; Schiemann, Kai ; TePoele, Robert ; de Haven Brandon, Alexis ; Mallinger, Aurélie ; Schneider, Richard ; Schwarz, Daniel ; Waalboer, Dennis ; Czodrowski, Paul ; Schneider, Klaus

There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.

26 Feb 2015·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of Potent, Orally Bioavailable, Small-Molecule Inhibitors of WNT Signaling from a Cell-Based Pathway Screen

Q1 · MEDICINE

Article

Author: De Haven Brandon, Alexis ; Clarke, Paul A. ; Henley, Alan T. ; Adeniji-Popoola, Olajumoke ; Smith, Elizabeth ; Wood, Bozena ; Ortiz-Ruiz, Maria-Jesus ; Poeschke, Oliver ; Georgi, Katrin ; Eccles, Suzanne A. ; Wienke, Dirk ; Waalboer, Dennis ; Court, William ; Leuthner, Birgitta ; Aherne, Wynne ; TePoele, Robert ; Stieber, Frank ; Crumpler, Simon ; Esdar, Christina ; Raynaud, Florence ; Mallinger, Aurélie ; Hobbs, Steve ; Dale, Trevor ; Box, Gary ; Schiemann, Kai ; Valenti, Melanie ; Rohdich, Felix ; Thai, Ching ; Pichowicz, Mark ; Workman, Paul ; Stubbs, Mark ; Blagg, Julian

WNT signaling is frequently deregulated in malignancy, particularly in colon cancer, and plays a key role in the generation and maintenance of cancer stem cells. We report the discovery and optimization of a 3,4,5-trisubstituted pyridine 9 using a high-throughput cell-based reporter assay of WNT pathway activity. We demonstrate a twisted conformation about the pyridine-piperidine bond of 9 by small-molecule X-ray crystallography. Medicinal chemistry optimization to maintain this twisted conformation, cognisant of physicochemical properties likely to maintain good cell permeability, led to 74 (CCT251545), a potent small-molecule inhibitor of WNT signaling with good oral pharmacokinetics. We demonstrate inhibition of WNT pathway activity in a solid human tumor xenograft model with evidence for tumor growth inhibition following oral dosing. This work provides a successful example of hypothesis-driven medicinal chemistry optimization from a singleton hit against a cell-based pathway assay without knowledge of the biochemical target.

100 Deals associated with CCT-251545

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 2	GB	University of Cardiff	13 Feb 2015
Neoplasms	Phase 2	DK	Merck KGaA	13 Feb 2015
Neoplasms	Phase 2	GB	Cancer Research UK Cancer Therapeutics Unit	13 Feb 2015

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