CAMBRIDGE, Mass.--(BUSINESS WIRE)--H3 Biomedicine Inc., a clinical stage biopharmaceutical company specializing in the discovery and development of precision medicines for oncology and a member of Eisai’s global Oncology Business Group, announced today that data on one of its pre-clinical programs has been published in the current issue of Nature Communications (https://www.nature.com/articles/ncomms15522 The title of the paper is “Splicing Modulators Act at the Branch Point Adenosine Binding Pocket Defined by the PHF5A-SF3b Complex,” which was composed by H3 scientists who are part of the company’s Drug Discovery team.
“This new research comes from H3’s novel drug discovery platform around the spliceosome and represents a unique finding that may be impactful within the area of RNA splicing-modulating small molecule drug discovery” said Ping Zhu, Ph.D., Executive Director, Head of Target Discovery & Genomics. “Scientists at H3 have uncovered PHF5A as a novel target of splicing modulators, which forms a central node with SF3B1 to regulate pre-mRNA splicing.”
The publication reports that:
- Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074 and SF3B1-V1078 confer resistance to splicing modulators pladienolide, herboxidiene and spliceostatin.
- RNA-sequencing analysis reveals that PHF5A-Y36C has minimal effect on basal splicing, but inhibits the global action of splicing modulators.
- PHF5A-Y36C alters splicing modulator-induced intron-retention/exon-skipping profile, which correlates with the differential GC content between adjacent introns and exons.
- The crystal structure of human PHF5A demonstrating that Y36 is located on a highly conserved surface.
- Analysis of the cryo-EM spliceosome Bact complex shows that the resistance mutations cluster in a pocket surrounding the branch point adenosine, suggesting a competitive mode of action.
- Collectively, we propose that PHF5A–SF3B1 forms a central node for binding to these splicing modulators.
“The mechanistic understanding of splicing modulators that H3’s research team continues to pioneer is the basis for the further development of novel therapies where there is significant unmet medical need” said Peter Smith, Ph.D., Chief Scientific Officer at H3 Biomedicine. “We are excited about the ongoing findings in our work focusing on the RNA splicing platform that remains central to the company’s oncology research program.
About H3 Biomedicine Splicing Platform
H3 Biomedicine has built a drug discovery platform that identifies small molecules and Splice Modulator Loaded Antibodies (SMLAs) capable of modulating RNA splicing for the potential treatment of cancer. An integrated research program starts with large scale analytics of cancer patient data to discover driver RNA splicing alterations in defined populations. Our target modulation approach uses structural, biochemical and cell-based methodologies to identify the appropriate modulation strategy to drug driver RNA splicing events. Translational research, diagnostics and preclinical development engines rapidly transform proof-of-concept compounds into investigational new agents for clinical development.
About H3 Biomedicine Inc.
H3 Biomedicine is a Cambridge, Massachusetts-based biopharmaceutical company specializing in the discovery and development of precision oncology treatments, which was established as a subsidiary of Eisai’s U.S. pharmaceutical operation, Eisai Inc. Leveraging this collaboration with Eisai Co., Ltd., who through this partnership provides essential research funding and access to the capabilities and resources of this global pharmaceutical company, H3 Biomedicine combines long-term vision with operational independence. Using modern synthetic chemistry, chemical biology and human genetics, H3 Biomedicine seeks to bring the next generation of cancer treatments to market with the goal of improving the lives of patients. For more information, please visit www.h3biomedicine.com.