H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers

Nat Med. 2018 May;24(4):497-504. doi: 10.1038/nm.4493. Epub 2018 Feb 19.

Abstract

Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor-encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Administration, Oral
  • Animals
  • Base Sequence
  • Humans
  • Introns / genetics
  • K562 Cells
  • Leukemia / genetics
  • Leukemia / pathology
  • Mice
  • Mutation
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Piperazines / administration & dosage
  • Piperazines / pharmacology*
  • Pyridines / administration & dosage
  • Pyridines / pharmacology*
  • RNA Splicing / drug effects
  • RNA Splicing / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Small Molecule Libraries / pharmacology
  • Small Molecule Libraries / therapeutic use*
  • Spliceosomes / genetics*
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • H3B-8800
  • Piperazines
  • Pyridines
  • RNA, Messenger
  • Small Molecule Libraries