Harvard Catalyst Profiles

University of South Carolina, Columbia, SC USA	PhD	06/2022	Drug Discovery and Biomedical Sciences
East Tennessee State University, Johnson City	MS	08/2014	Biology

In my PhD dissertation work, I generated fragment-ligated inhibitory peptides (FLIPs) by replacing key residues of two PLK1 substrate peptides, with drug-like small molecule fragments. Experimental testing and further modeling produced completely non-peptidic compounds named abbapolins. Through my initiative and while investigating their cellular activity, I discovered the novel mechanism of action, that abbapolins caused a striking dose dependent reduction in PLK1 protein levels; the loss being partially due to proteasome mediated degradation (the mechanism is under US patent). Interestingly the degradation of PLK1 caused by abbapolin binding does not require the conjugation of an E3 ligase ligand for ubiquitination. Again, through my initiative, I evaluated the phosphorylation status of translationally controlled tumor protein (TCTP), a specific PLK1 substrate, in abbapolin treated cells. I made the novel observation that abbapolins produced a dose dependent reduction in p-TCTP signal without affecting total levels of TCTP (PBD binder abbapolins allosterically modulate catalytic domain). Moreover, I studied the therapeutic potential of abbapolins in the resistant cells with PLK1 catalytic inhibitors (C67V PLK1 mutant). The resistant cells showed sensitivity to abbapolins.

I report novel findings during mitosis inferred from my collective data, namely that catalytic binding by BI2536 or volasertib unexpectedly decreased soluble PLK1 as determined by CETSA, inferring induction of a conformational change in intracellular PLK1 . In addition to that, in vivo pharmacokinetic study showed that abbapolins have measurable blood levels in mice injected at 50 mg/kg by oral gavage. Xenograft study showed that abbapolins inhibited the growth of prostate tumors.
Taken together, my doctoral dissertation presented small molecule inhibitors targeting the PBD of PLK1 and non-ATP competitive are a potentially compelling alternative to catalytic-based inhibitors with novel mechanism of actions and drug-like properties.

As a Postdoctoral Research Fellow at Massachusetts General Hospital, and Harvard Medical School, I am working on two major projects that involve therapeutic development against the lymphoma and multiple myeloma. They are 1) PAX5 requirement for lymphoma cell survival, and development of therapeutic to target this dependency, and 2) What are genomic/epigenomic markers of CBP/p300 dependency and or dCBP-1 (Protac molecule that degrade CBP and p300) sensitivity/resistance?.