Physiology Seminar TODAY (Nov. 13): Dr. Chao-Yie Yang presents “Targeting RNA splicing Factors in Hematological Malignancies” Associate Professor, Pharmaceutical Sciences

The Department of Physiology Seminar Series continues this week!

The Department of Physiology is pleased to announce Dr. Chao-Yie Yang, Associate Professor, Pharmaceutical Sciences, UTHSC College of Pharmacy will be presenting his seminar titled:

"Targeting RNA splicing Factors in Hematological Malignancies" on Thursday, Nov. 13, from 3:30-5 p.m. in Freeman Auditorium, located inside the 930 Madison Building on the third floor. Please join us!

Refreshments will be provided. All attendees please sign in.

Talk Summary
Mutations in a group of genes involved in RNA splicing−SF3B1, U2AF1, SRSF2, and ZRSR2− are frequently found in myeloid neoplasms, including MDS and secondary AML (sAML). These mutations alter splicing patterns in cells and generate aberrant protein isoforms that contribute to tumor development and progression. Pharmacologically targeting these splicing factors in hematological malignancies to improve patient outcomes has emerged as a promising therapeutic strategy. Although two classes of compounds have entered clinical trials, the primary endpoints of these studies were not achieved, underscoring the need for new targeting approaches to benefit patients harboring splicing factor mutations.

My lab has focused on discovering and developing compounds that target U2 small nuclear RNA Auxiliary Factor 1 (U2AF1) over the past few years. U2AF1 is a key factor that recognizes the 3' splice site and defines the intron-exon boundary during RNA splicing. Mutations in U2AF1 in myeloid neoplasms are generally associated with poor prognosis.

In this seminar, Dr. Yang will present his lab's progress in inhibitor development and discuss the mechanisms underlying the antitumor activities of our inhibitors. Notably, one U2AF1 inhibitor induced cell line-dependent cell cycle arrest, impaired lysosome acidification and inhibited autophagy. RNA-seq analysis of cell lines treated with two classes of inhibitors revealed convergent downregulation of genes in E2F targets, Myc targets, and G2/M checkpoint pathways. They also observed alteration in splicing patterns of a subset of genes involved in RNA processing by both compounds.

Currently, no U2AF1 inhibitors have been reported. This study elucidates the cellular responses of leukemia cells to small-molecule U2AF1 inhibitors and provides new insights into the therapeutic development of targeting U2AF1 in blood cancers.

Biography
Dr. Yang received his PhD training in Theoretical Chemistry at Case Western Reserve University and changed his research focus to drug design and development by working with his mentor, Dr. Shaomeng Wang, at University of Michigan. Through his 19 years of research at University of Michigan, he has contributed to many drug development projects and several compounds have entered clinical trials. One of the compounds, Lisaftoclax, has been approved to treat CLL/SLL in China in 2025. Since 2019, he moved to UTHSC College of Pharmacy to establish his research lab. Dr. Yang's research focus is to develop chemical inhibitors/probes to target protein targets playing important roles in cancers and immune mediated diseases. Dr. Yang's lab integrates computational modeling, medicinal chemistry, biochemical and cell-based assays in the inhibitor/drug development projects.