Dr. Michael Olson - MRCK kinases and MICAL1 monooxygenase: Actin cytoskeleton regulators as cancer drug targets
Tuesday Seminar Series
Tuesday, October 18, 2022 | 4:00 PM | MSB 4171
MRCK kinases and MICAL1 monooxygenase: Actin cytoskeleton regulators as cancer drug targets
Presented by:
Michael Olson Ph.D.
Dept. of Chemistry and Biology, Toronto Metropolitan University
Dept. of Pharmacology & Toxicology, University of Toronto
The actin cytoskeleton provides the structural underpinning that determines cell shape. Dynamic changes in cytoskeleton organization affect numerous cell functions, including phagocytosis, adhesion, motility and cell division. The cytoskeleton also plays roles in cell survival and proliferation. Changes in the activity of key cytoskeleton regulators contribute to cancer, making them potential cancer drug targets.
Acting downstream of the CDC42 GTPase, the MRCK kinases phosphorylate substrates that promote actin-myosin cytoskeleton contractile force generation. Given that that MRCK expression was increased in some cancers, we endeavoured to discover MRCK small molecule inhibitors. Fragment based screening and medicinal chemistry ultimately produced the first potent and selective MRCK inhibitor BDP9066. Cell based profiling revealed that BDP9066 altered actin cytoskeleton organization, changed cell morphology and reduced 2D cell migration and invasion into 3D extracellular matrix. Mouse models of skin cancer and brain tumours revealed the beneficial effects of BDP9066 administration. BDP9066 has also recently been shown to be a novel therapy for high grade serous ovarian cancer.
Cytoskeleton organization is also regulated by actin post-translational modifications. The MICAL family (MICAL1, MICAL2, MICAL3) of monooxygenases modify actin structures through direct oxidation of methionine residues. CRISPR/Cas9-mediated gene deletion of MICAL1 in human breast cancer cells demonstrated a role in cytoskeleton organization and cell motility. Growth of control and knockout cells as orthotopic xenograft tumours also revealed a requirement for MICAL1 in tumour growth. In vitro screening of candidate compounds identified small molecule inhibitors, supporting the druggability of MICAL1 as a potential cancer therapeutic target.
Hosted by: Lenny Salmena
Please contact the Department directly (leonardo.salmena@utoronto.ca) if you require any accommodation(s) in order to attend this event, and we will work with you to create the appropriate arrangements.