Abstract 3839: A small-molecule inhibitor of the β-catenin-TCF4 interaction suppresses colorectal cancer growth in vitro and in vivo

Disrupting the interactions between Hsp90 and Cdc37 is emerging as an alternative and specific way to regulate the Hsp90 chaperone cycle in a manner not involving adenosine triphosphatase inhibition. Here, we identified DDO-5936 as a small-molecule inhibitor of the Hsp90-Cdc37 protein-protein interaction (PPI) in colorectal cancer. DDO-5936 disrupted the Hsp90-Cdc37 PPI both in vitro and in vivo via binding to a previously unknown site on Hsp90 involving Glu47, one of the binding determinants for the Hsp90-Cdc37 PPI, leading to selective down-regulation of Hsp90 kinase clients in HCT116 cells. In addition, inhibition of Hsp90-Cdc37 complex formation by DDO-5936 resulted in a remarkable cyclin-dependent kinase 4 decrease and consequent inhibition of cell proliferation through Cdc37-dependent cell cycle arrest. Together, our results demonstrated DDO-5936 as an identified specific small-molecule inhibitor of the Hsp90-Cdc37 PPI that could be used to comprehensively investigate alternative approaches targeting Hsp90 chaperone cycles for cancer therapy.

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A Novel Small-Molecule Inhibitor of Mcl-1 Blocks Pancreatic Cancer Growth In Vitro and In Vivo

Molecular Cancer Therapeutics ◽

10.1158/1535-7163.mct-12-0767 ◽

2013 ◽

Vol 13 (3) ◽

pp. 565-575 ◽

Cited By ~ 109

Author(s):

Fardokht Abulwerdi ◽

Chenzhong Liao ◽

Meilan Liu ◽

Asfar S. Azmi ◽

Amro Aboukameel ◽

...

Keyword(s):

Pancreatic Cancer ◽

Small Molecule ◽

Small Molecule Inhibitor ◽

Cancer Growth ◽

Molecule Inhibitor

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Pharmacological targeting PTK6 inhibits the JAK2/STAT3 sustained stemness and reverses chemoresistance of colorectal cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02059-6 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Chaoqun Liu ◽

Zhihua Pan ◽

Qian Chen ◽

Zetao Chen ◽

Weiwei Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Small Molecule ◽

Nude Mice ◽

Small Molecule Inhibitor ◽

Loss Of Function ◽

Pharmacological Inhibition ◽

Stat3 Signaling ◽

Molecule Inhibitor

Abstract Background Chemoresistance is the major cause of chemotherapy failure in patients with colorectal cancer (CRC). Protein tyrosine kinase 6 (PTK6) is aberrantly overexpressed in clinical CRC tissues undergoing chemotherapy. We studied if PTK6 contributed to the chemoresistance of CRC in human and mice. Methods We obtained tissue samples from patients with CRC and measured the expression of PTK6 by immunohistochemistry. Gain- and loss-of-function assays were performed to study the biological functions of PTK6. We constructed the FLAG-tagged wild type (WT), kinase-dead, and inhibition-defective recombinant mutants of PTK6 to study the effect phosphorylated activation of PTK6 played on CRC cell stemness and chemoresistance. We used small molecule inhibitor XMU-MP-2 to test the influence of PTK6 on sensitivity of CRC cells to 5-FU/L-OHP in both nude mouse and patient-derived xenograft (PDX) animal models. Results PTK6 is overexpressed in CRC tissues and plays a stimulatory role in the proliferation and chemoresistance of CRC cells both in vitro and in vivo. PTK6, especially the phosphorylated PTK6, can promote the stemness of CRC cells through interacting with JAK2 and phosphorylating it to activate the JAK2/STAT3 signaling. Pharmacological inhibition of PTK6 using XMU-MP-2 effectively reduces the stemness property of CRC cells and improves its chemosensitivity to 5-FU/L-OHP in both nude mice subcutaneously implanted tumor model and PDX model constructed with NOD-SCID mice. Conclusions PTK6 interacts with JAK2 and phosphorylates it to activate JAK2/STAT3 signaling to promote the stemness and chemoresistance of CRC cells. Pharmacological inhibition of PTK6 by small molecule inhibitor dramatically enhances the sensitivity to chemotherapy in nude mice and PDX models.

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