Abstract 5564: Total synthesis of 6-deoxypladienolide D and assessment of splicing inhibitory activity in a mutant SF3B1 cancer cell line

Abstract

Abstract Hotspot mutations in several components of the spliceosome have been reported in various hematological (CLL, MDS, etc.) and solid tumor (melanoma, pancreatic, etc.) malignancies. SF3B1 is a component of the U2 snRNP complex of the spliceosome and is involved in the recognition of 3′-splice sites during early spliceosomal assembly. We and others have demonstrated that mutations in SF3B1 result in neomorphic activity and trigger the production of aberrantly spliced transcripts. Thus, the discovery of small molecule modulators of SF3B1 splicing activity may have therapeutic potential in cancers harboring SF3B1 mutations. Members of the pladienolide family of natural products have been shown to affect RNA splicing through interaction with SF3B1. We have found that one particular natural product in this family, 6-deoxypladienolide D, demonstrates potent growth inhibition and cellular lethality in Panc 05.04 cells (a hotspot mutant SF3B1 cancer cell line). Due to the limited natural supply of 6-deoxypladienolide D and our interest in identifying chemical matter able to modulate splicing in these newly-identified mutant SF3B1 cancers, a total synthesis of 6-deoxypladienolide D using versatile and modular fragments was initiated. We will describe the first total synthesis of the natural product 6-deoxypladienolide D. Two noteworthy synthetic attributes are: 1) a late-stage allylic oxidation which proceeds with full chemo-, regio-, and diastereoselectivity and 2) the use of cost-effective starting materials and reagents to enable access to 6-deoxypladienolide D and its analogs for biological evaluation. We will show that 6-deoxypladienolide D demonstrates: 1) high binding affinity to the SF3b complex, 2) ability to modulate canonical pre-mRNA splicing, and 3) modulation of aberrant splicing induced by mutant SF3B1. Citation Format: Kenzo Arai, Silvia Buonamici, Betty Chan, Laura Corson, Atsushi Endo, Baudouin Gerard, Ming-Hong Hao, Craig Karr, Kazunobu Kira, Linda Lee, Xiang Liu, Jason T. Lowe, Tuoping Luo, Lisa A. Marcaurelle, Yoshiharu Mizui, Marta Nevalainen, Morgan Welzel O'Shea, Eun Sun Park, Samantha A. Perino, Sudeep Prajapati, Mingde Shan, Peter G. Smith, Parcharee Tivitmahaisoon, John Yuan Wang, Markus Warmuth, Kuo-Ming Wu, Lihua Yu, Huiming Zhang, Guo Zhu Zheng, Gregg F. Keaney. Total synthesis of 6-deoxypladienolide D and assessment of splicing inhibitory activity in a mutant SF3B1 cancer cell line. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5564. doi:10.1158/1538-7445.AM2015-5564