A Comprehensive Overview of Structure‐Activity Relationships of Small‐Molecule Splicing Modulators Targeting SF3B1 as Anticancer Agents

Abstract

The pre‐mRNA splicing factor SF3B1 shows recurrent mutations among hematologic malignancies and some solid tumors. In 2007, the identification of two cytotoxic natural products, which showed splicing inhibition by binding to SF3b, prompted the development of small‐molecule splicing modulators of SF3B1 as therapeutics for cancer. Recent studies suggested that spliceosome‐mutant cells are preferentially sensitive to pharmacologic splicing modulation; therefore, exploring the clinical utility of splicing modulator therapies in patients with spliceosome‐mutant hematologic malignancies who have failed current therapies is greatly needed, as these patients have few treatment options. H3B‐8800 had unique pharmacological activity and exhibited favorable data in phase I clinical trials to treat patients with advanced myeloid malignancies, indicating that further clinical trials are promising. The most established small‐molecule modulators of SF3B1 can be categorized into three classes: the bicycles, the monopyranes, and the 12‐membered macrolides. This review provides a comprehensive overview of the structure‐activity relationships of small‐molecule SF3B1 modulators, with a detailed analysis of interactions between modulators and protein binding pocket. The future strategy for splicing modulators development is also discussed.

Rewards of divergence in sequences, 3-D structures and dynamics of yeast and human spliceosome SF3b complexes

“…SF3b1 is directly involved in BPS recognition and hence mutations or small molecules binding in the SF3b1 are known to affect BPS selection, leading to alternative splicing ( Alsafadi et al., 2016 ; Corrionero et al., 2011 ; Darman et al., 2015 ; Maguire et al., 2015 ; Seiler et al., 2018 ; Zhang and Meng, 2020 ). Further, SF3b1 contributes to the regulatory mechanism of alternative splicing by serving as a scaffold for the binding of alternative splicing modulators at its N-terminal extension viz.…”

Stereochemical Control of Splice Modulation in FD-895 Analogues

“…18,19 These studies have led to a remarkable level of structure−activity relationship (SAR) data that defines how each of these molecules adopts a consensus motif that uniquely positions itself into the core SF3B complex of the spliceosome. 20,21 Recognized since their discovery, the high potency and tumor cell selectivity of these analogues has ultimately led to the entry of two Phase I clinical trials on semi-synthetic analogues E7107 (3a, Figure 2) and H3B-8800 (3b). 22,23 While both trials were unsuccessful, the promise of this class remains, and medicinal chemical efforts have continued to tune the metabolic stability and splice modulatory activity of this class, with the ultimate goal of realizing active analogues that can serve either as primary therapeutics or as the active agents in antibody−drug conjugates.…”

Total Syntheses of Pladienolide-Derived Spliceosome Modulators

“…Owing to a growing interest in RNA splicing for drug discovery, a number of studies and patents have been reported, including review articles that (partially) cover the biological features and structure–activity relationship of pladienolides [ 40 , 41 , 42 , 43 , 44 ]. In this review, we provide a comprehensive overview of the total synthesis of pladienolides or their core structures, with a detailed analysis of the synthetic routes.…”