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

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.

• Authors: Michael Seiler, Akihide Yoshimi, Rachel Darman, Betty Chan, Gregg Keaney, Michael Thomas, Anant A Agrawal, Benjamin Caleb, Alfredo Csibi, Eckley Sean, Peter Fekkes, Craig Karr, Virginia Klimek, George Lai, Linda Lee, Pavan Kumar, Stanley Chun-Wei Lee, Xiang Liu, Crystal Mackenzie, Carol Meeske, Yoshiharu Mizui, Eric Padron, Eunice Park, Ermira Pazolli, Shouyong Peng, Sudeep Prajapati, Justin Taylor, Teng Teng, John Wang, Markus Warmuth, Huilan Yao, Lihua Yu, Ping Zhu, Omar Abdel-Wahab, Peter G Smith, Silvia Buonamici
• Journal: Nature medicine (Nat Med) Vol. 24 Issue 4 Pg. 497-504 (05 2018) ISSN: 1546-170X [Electronic] United States
• PMID: 29457796 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

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

Topics

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