The CLK inhibitor SM08502 induces anti-tumor activity and reduces Wnt pathway gene expression in gastrointestinal cancer models
Betty Y Tam, Kevin Chiu, Heekyung Chung, Carine Bossard, John Duc Nguyen, Emily Creger, Brian W Eastman, Chi Ching Mak, Maureen Ibanez, Abdullah Ghias, Joseph Cahiwat, Long Do, Shawn Cho, Jackie Nguyen, Vishal Deshmukh, Josh Stewart, Chiao-Wen Chen, Charlene Barroga, Luis Dellamary, Sunil K Kc, Timothy J Phalen, John Hood, Steven Cha, Yusuf Yazici, Betty Y Tam, Kevin Chiu, Heekyung Chung, Carine Bossard, John Duc Nguyen, Emily Creger, Brian W Eastman, Chi Ching Mak, Maureen Ibanez, Abdullah Ghias, Joseph Cahiwat, Long Do, Shawn Cho, Jackie Nguyen, Vishal Deshmukh, Josh Stewart, Chiao-Wen Chen, Charlene Barroga, Luis Dellamary, Sunil K Kc, Timothy J Phalen, John Hood, Steven Cha, Yusuf Yazici
Abstract
The Wnt/β-catenin signaling pathway is aberrantly activated in colorectal (CRC) and many other cancers, and novel strategies for effectively targeting it may be needed due to its complexity. In this report, SM08502, a novel small molecule in clinical development for the treatment of solid tumors, was shown to reduce Wnt pathway signaling and gene expression through potent inhibition of CDC-like kinase (CLK) activity. SM08502 inhibited serine and arginine rich splicing factor (SRSF) phosphorylation and disrupted spliceosome activity, which was associated with inhibition of Wnt pathway-related gene and protein expression. Additionally, SM08502 induced the generation of splicing variants of Wnt pathway genes, suggesting that its mechanism for inhibition of gene expression includes effects on alternative splicing. Orally administered SM08502 significantly inhibited growth of gastrointestinal tumors and decreased SRSF phosphorylation and Wnt pathway gene expression in xenograft mouse models. These data implicate CLKs in the regulation of Wnt signaling and represent a novel strategy for inhibiting Wnt pathway gene expression in cancers. SM08502 is a first-in-class CLK inhibitor being investigated in a Phase 1 clinical trial for subjects with advanced solid tumors (NCT03355066).
Keywords: Alternative splicing; Beta-catenin; CDC-Like kinase; Colorectal cancer; SRSF.
Conflict of interest statement
Declaration of competing interest Samumed LLC salary and equity: B.Y.T., K.C., H.C., C.B., E.C., M.I., A.G., J.C., L.D., S.Cho, J.N., V.D., J.S., C.W.C., C.Ba., L.D., B.W.E., C.C.M., S.K.K.C., J.H., T.J.P., S.Cha, Y.Y. Patent # WO2017189829 was filed related to results in this paper.
Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.
Source: PubMed