Grad Student Spotlight Seminar: Omar Qassem and Lei Wang

Omar Qassem

Omar Qassem, TSD Grad Student Spotlight Seminar, in the PULSe – Department of Biological Sciences department at Purdue University, will be a speaker for the PICR Seminar Series. This event is hosted by John Tesmer.

Structural and biochemical analysis of adenylyl cyclase 5 inhibition by G alpha i subunit

Adenylyl cyclases (ACs) convert ATP into cAMP, a central second messenger in G protein-coupled receptor signaling. Dysregulation of cAMP has been linked to a range of pathophysiological conditions, including cancer, making components of this pathway important targets for therapeutic development. This work focuses on AC5, an isoform regulated by multiple heterotrimeric G proteins and considered a key integrator of extracellular signaling. In mouse models, AC5 knockout has been associated with reduced age-related tumor incidence, decreased tumor growth and angiogenesis, and increased apoptosis.

All membrane-bound AC isoforms are activated by Gαs and share nearly identical active sites, suggesting that achieving AC5-selective targeting will require a deeper understanding of how it responds to Gαi and Gβγ. Recent cryo-EM studies indicate that AC5 forms homodimers in the absence of Gβγ. Preliminary reconstructions further show that Gαi binds to these homodimers, supporting a model in which Gβγ, an activator, and Gαi, an inhibitor, regulate AC5 activity by controlling the equilibrium between monomeric and homodimeric states.

Lei Wang

Lei Wang, postdoctoral scholar, will present as part of the TSD Graduate Student Spotlight Seminar series hosted by PULSE in the Department of Biological Sciences at Purdue University.

Peptide inhibitors of the CBX8 chromodomain using covalent tyrosine conjugation and cation–pi interaction modulation

CBX8, a member of the Polycomb group proteins, plays a key role in repressing genes involved in cellular differentiation by recruiting the Polycomb Repressive Complex 1 (PRC1) to chromatin. This study explores two strategies to improve inhibitor design targeting the CBX8 chromodomain. First, researchers evaluate cyclic imine Mannich electrophiles as covalent warheads that selectively react with a tyrosine residue near the binding pocket. These inhibitors demonstrate improved potency and selectivity in both in vitro and cellular models, with chemo-proteomic analysis confirming selective labeling of CBX8. This represents a novel application of this chemistry in target covalent inhibitors.

In a second approach, the study examines how modifying the electronic properties of alkylated lysine residues can strengthen cation–pi interactions within the chromodomain’s aromatic cage. By synthesizing lysine analogues with a range of pKa values, researchers show that reducing electron density can enhance binding affinity by up to tenfold. This strategy offers a broadly applicable method for optimizing molecular interactions in medicinal chemistry.