University of Dundee

"Anticancer Sulfonamides Induce Selective Protein Degradation of Splicing Factor CAPERalpha (RBM39)"

Event Date: 
Wednesday, November 29, 2017 - 11:00 to 12:00
Event Location: 
CTIR Sir Kenneth and Lady Noreen Murray Seminar Room
Host: 
Professor Alessio Ciulli FRSC
Event Speaker: 
Dr Takashi Owa
Institution: 
Chief Discovery Officer of Eisai Oncology Business Group
Event Type: 
Seminar
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All Welcome!

 

 

Dr. Takashi Owa currently serves as the Chief Medicine Creation Officer and Chief Discovery Officer of Eisai Oncology Business Group as well as a member of Board of Directors for Eisai Inc., H3 Biomedicine Inc., and Morphotek Inc. in the United States. In this role, he is responsible for leading the worldwide R&D operations of Eisai Oncology. Since 2013, he has also served as a Vice President and Corporate Officer of Eisai Co., Ltd. in Japan.

He received his Ph.D. in 1991 from the University of Tokyo in synthetic organic chemistry and cancer biology on the bleomycin class of anticancer agents, and joined Eisai Co., Ltd in the same year as a research scientist at Tsukuba Research Laboratories. In addition, he studied as a post-doctoral visiting scientist from 1996 to 1998 at Professor Stuart Schreiber’s Laboratory in the Department of Chemistry and Chemical Biology of Harvard University, where he focused on chemical biology with histone deacetylase (HDAC) inhibitors as well as the anticancer marine product ecteinascidin 743 (Yondelis/trabectedin) and its synthetic analog phthalascidin 650.

Since his relocation to the United States in 2009, He has been in charge of the full product creation cycle from discovery research to clinical development for regulatory approval of innovative oncology drugs in Eisai, including anticancer sulfonamides E7070/indisulam and E7820, the splicing factor SF3B modulator E7107 as well as two approved drugs Halaven/eribulin (microtubule dynamics inhibitor) and Lenvima/lenvatinib (VEGFR/FGFR/PDGFRa/RET/KIT tyrosine kinase inhibitor). He has been honored by the Pharmaceutical Society of Japan with three awards for his work. Since 2015, He has also been serving as a Visiting Professor at the Graduate School of Pharmaceutical Sciences, the University of Tokyo.

Title of my talk:

Anticancer Sulfonamides Induce Selective Protein Degradation of Splicing Factor CAPERa (RBM39)

Abstract:

The aryl sulfonamide drugs E7820, E7070 (indisulam), and chloroquinoxaline sulfonamide (CQS) are toxic to a subset of cancer cell lines and achieve clinical responses in a small subset of patients with advanced solid tumors. However, their mechanisms of action have yet to be fully understood. Using proteomic profiling, we found that the aryl sulfonamide drugs promoted proteasomal degradation of the U2AF-related splicing factor CAPERα (also known as RBM39) in human colorectal carcinoma and myelogenous leukemia cell lines. Mechanistically, treatment with the aryl sulfonamide drugs resulted in recruitment of CAPERα to the CUL4–DCAF15 E3 ubiquitin ligase, where it was polyubiquitinated and targeted for proteasomal degradation. CRISPR/Cas9-mediated depletion of DCAF15 or mutations in CAPERα that disrupted CAPERα recruitment to CUL4–DCAF15 enhanced the stability of CAPERα and conferred resistance to the aryl sulfonamide drugs, indicating that CAPERα is essential for the antitumor effects of these drugs. Further, CAPERα depletion led to a change in the pattern of alternative splicing of VEGFA as well as altered expression of a number of target mRNAs, suggesting that aryl sulfonamides–mediated CAPERα degradation may profoundly affect pre-mRNA splicing. Collectively, these findings reveal a mechanism by which the aryl sulfonamide drugs exert anticancer effects via targeting of CAPERα, which is otherwise considered to be undruggable, and suggest that chemical intervention in protein homeostasis or small molecule–induced selective protein degradation may be therapeutic strategies to treat patients with cancer.

Reference: Uehara, T. et al. Nat. Chem. Biol. http://dx.doi.org/10/1038/nchembio.2363 (2017).