Murtaza is a chemical biologist that joined the Gray Lab in July 2021 as a postdoctoral researcher. He developed his love for medicinal chemistry and chemical biology at the undergraduate level at the University of Toronto Mississauga which then motivated him to pursue an MSc (York University, Supervisor: Prof. Edward Lee-Ruff, 2017) and PhD (University of Toronto Mississauga, Supervisor: Patrick T. Gunning, 2021) in the field. His PhD work involved the development of some of the most potent and selective HDAC8 inhibitors known-to-date. It incorporated inhibitors with L-shaped conformational constraints to compliment the L-shaped HDAC8 pocket. His current work at the Gray Lab revolves around the development of first-in-class covalent inhibitors for recently discovered epigenetic targets that have been shown to synergize with anticancer immunotherapy. Additionally, he is interested in developing small-molecule chemoproteomic tools that can potentially expand our ability to target otherwise undruggable proteins, by using protein-protein interactions for cross-labelling/drugging interacting proteins.
Nathanael Gray, Postdoctoral Faculty Sponsor
Development of HDAC Inhibitors Exhibiting Therapeutic Potential in T-Cell Prolymphocytic Leukemia
JOURNAL OF MEDICINAL CHEMISTRY
2021; 64 (12): 8486-8509
Epigenetic targeting has emerged as an efficacious therapy for hematological cancers. The rare and incurable T-cell prolymphocytic leukemia (T-PLL) is known for its aggressive clinical course. Current epigenetic agents such as histone deacetylase (HDAC) inhibitors are increasingly used for targeted therapy. Through a structure-activity relationship (SAR) study, we developed an HDAC6 inhibitor KT-531, which exhibited higher potency in T-PLL compared to other hematological cancers. KT-531 displayed strong HDAC6 inhibitory potency and selectivity, on-target biological activity, and a safe therapeutic window in nontransformed cell lines. In primary T-PLL patient cells, where HDAC6 was found to be overexpressed, KT-531 exhibited strong biological responses, and safety in healthy donor samples. Notably, combination studies in T-PLL patient samples demonstrated KT-531 synergizes with approved cancer drugs, bendamustine, idasanutlin, and venetoclax. Our work suggests HDAC inhibition in T-PLL could afford sufficient therapeutic windows to achieve durable remission either as stand-alone or in combination with targeted drugs.
View details for DOI 10.1021/acs.jmedchem.1c00420
View details for Web of Science ID 000668340800034
View details for PubMedID 34101461
View details for PubMedCentralID PMC8237267