A Small-Molecule Splicing Modulator Targets Spliceosome-Mutant Cells

Mutations in splicing factors, including SF3B1, U2AF1, and SRSF2, occur frequently in patients with myelodysplastic syndromes, chronic myelomonocytic leukemia (CMML), and chronic lymphocytic leukemia, and also occur in a variety of solid tumor types. Instead of producing a loss of function, these mutations produce aberrant splicing, such as usage of a cryptic 3′ splice site or altered exon inclusion/exclusion. Moreover, cancer cells bearing these mutations depend on wild-type spliceosome function for survival. Pharmacologic modulation of splicing has emerged as a potential therapeutic strategy in spliceosome-mutant malignancies, but the available splice modulators do not induce preferential lethality in spliceosome-mutant cells and are not orally bioavailable, limiting their potential for clinical development. To overcome these challenges, Seiler, Yoshimi, Darman, and colleagues used an iterative medicinal chemistry approach starting from pladienolide, a natural product that binds to and modulates the SF3b complex. This approached yielded H3B-8800, an orally bioavailable small molecule that bound to both wild-type and mutant spliceosomes, resulting in dose-dependent modulation of both canonical and aberrant splicing. Although H3B-8800 modulates the activity of both wild-type and mutant spliceosomes, it preferentially killed spliceosome-mutant cells. In vivo, H3B-8800 suppressed the growth of spliceosome-mutant, but not spliceosome wild-type, AML xenografts and AML and CMML patient-derived xenografts. RNA sequencing showed that H3B-8800 preferentially retains short and GC-rich introns, and these introns were enriched for genes encoding spliceosome components, providing a potential mechanism for the specific lethality of H3B-8800 toward spliceosome-mutant cells that are dependent on the function of wild-type spliceosomes for survival. The development of H3B-8800, an orally bioavailable small molecule that modulates splicing to induce selective killing of spliceosome-mutant cells, supports further clinical investigation of H3B-8800 for the treatment of patients with malignancies harboring RNA splicing factor mutations.

Seiler M, Yoshimi A, Darman R, Chan B, Keaney G, Thomas M, et al. H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. Nat Med 2018 Feb 19 [Epub ahead of print].

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