WEHI Special New Medicines and Diagnostics Seminar hosted by Professor Guillaume Lessene

Dr Duong Nhu

Senior Research Officer – Lessene Laboratory, New Medicines and Diagnostics division, WEHI

Development of BCL-XL-targeting PROTACs as anticancer agents with improved therapeutics window

L7W Seminar Room / Bundoora Large Boardroom

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Including Q&A session

Dr Duong Nhu completed her PhD at the WEHI/University of Melbourne in 2016 and undertook postdoctoral training at the University of Otago, focused on the development of chemical transformations to access natural products-inspired bioactive molecules. She then returned to WEHI to join the Chemical Biology division (now New Medicines and Diagnostics Division) in the Lessene laboratory. Duong’s research has centred on developing small molecules that potently induce the programmed-cell death pathway in heametological and solid cancers.

Evasion of apoptosis through overexpression of pro-survival proteins of the BCL-2 family (MCL-1, BCL-2 and BCL-X_L) is a hallmark of cancer. Inhibiting these proteins to reinstate cell death has become a validated cancer therapy, demonstrated by the FDA approved BCL-2 inhibitor venetoclax for treatment of leukemias.[1, 2] Another pro-survival protein, BCL-X_L, has been implicated in driving chemoresistance, including resistance to venetoclax, and its overexpression is also evident in various solid tumours and a subset of haematological cancers.[3, 4] While BCL-X_L is an attractive target, clinical applications of potent and selective inhibitors such as ABT-263 and A1331852 are hampered by adverse thrombocytopenia, as circulating platelets depend on BCL-X_L for survival.[5, 6]

We propose that induction of BCL-X_L degradation, using proteolysis-targeting chimeras (PROTACs) which engage E3 ligases minimally expressed in platelets[7, 8], could confer an improved therapeutic window over conventional inhibition. Here, we report our efforts to develop BCL-X_L-recruiting PROTACs derived from the potent and orally available BCL-X_L inhibitor A1331852. These compounds demonstrated nanomolar potency in inducing BCL-X_L degradation and apoptosis-dependent cell death in BCL-X_L dependent cancer cell lines. Gratifyingly, our lead PROTAC was well tolerated in an in vivo xenograft mouse model of breast cancer and effectively degraded BCL-X_L in vivo. Most importantly, the lead candidate outperformed A1331852 in tumour eradication and exhibited reduced platelet toxicity.

1.             Lessene, G., P.E. Czabotar, and P.M. Colman, BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov, 2008. 7(12): p. 989-1000.

2.             Lasica, M. and M.A. Anderson, Review of Venetoclax in CLL, AML and Multiple Myeloma. J Pers Med, 2021. 11(6).

3.             Held, L., C. Siu, and M. Shadman, Venetoclax as a therapeutic option for the treatment of chronic lymphocytic leukemia: the evidence so far. Expert Opin Pharmacother, 2021. 22(6): p. 655-665.

4.             Trisciuoglio, D., et al., BCL-X(L) overexpression promotes tumor progression-associated properties. Cell Death Dis, 2017. 8(12): p. 3216.

5.             Wang, L., et al., Discovery of A-1331852, a First-in-Class, Potent, and Orally-Bioavailable BCL-XL Inhibitor. ACS Med Chem Lett, 2020. 11(10): p. 1829-1836.

6.             Mason, K.D., et al., Programmed anuclear cell death delimits platelet life span. Cell, 2007. 128(6): p. 1173-86.

7.             Bray, P.F., et al., The complex transcriptional landscape of the anucleate human platelet. BMC Genomics, 2013. 14: p. 1.

8.             Kissopoulou, A., et al., Next generation sequencing analysis of human platelet PolyA+ mRNAs and rRNA-depleted total RNA. PLoS One, 2013. 8(12): p. e81809.

All welcome!