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Synergy in a Single Molecule: Chimeric Small Molecule Inhibitors of PI3K and BET Bromodomains for the Treatment of Myc-driven Lymphoma.

CL_16 Rainforest Walk, Room S12, Theatre (Bldg 25)

Zoom: https://monash.zoom.us/j/81063358685
ID: 81063358685
Passcode: 714030

Targeted inhibitors of bromodomain and extraterminal (BET)-bromodomains and phosphatidylinositol-3-kinase (PI3K) signalling demonstrate potent but self-limited anti-lymphoma activity as single-agents in the context of cMYC-dysregulation. However, combined PI3K and BET inhibition imparts synergistic anti-cancer activity with the potential for more sustained disease responses due to the mutual
antagonism of compensatory epigenetic and signalling networks. This presentation will describe the mechanistic and therapeutic validation of
rationally designed dual PI3K/BET bromodomain inhibitors, built by linkage of established PI3K and BET inhibitor pharmacophores. Our lead
candidate demonstrates high selectivity, nanomolar range cellular potency and compelling in vivo efficacy, including curative responses in
the aggressive Em-Myc lymphoma model. These studies further support the therapeutic strategy of combined PI3K and BET inhibition and provide
a potential step-change in approach to orthogonal MYC antagonism using optimised chimeric small molecule technology.

Prof Jake Shortt is a clinician scientist who is co-appointed to Monash University and Monash Health where he leads Haematology Research
and the Blood Cancer Therapeutics Laboratory. His research focuses on discovering and drugging new targets in haematological malignancies –
with a disease focus on lymphoma and myeloma. Therapeutic areas of interest include epigenetically active small molecules and pro-survival
signalling cascades. In addition to preclinical discovery, he is a Principal Investigator on investigator-initiated, collaborative group and industry-
sponsored trials from phase 1 to 3 in myeloma, myelodysplasia, acute leukaemia and T-cell lymphoma.

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