Journal article

Preclinical small molecule WEHI-7326 overcomes drug resistance and elicits response in patient-derived xenograft models of human treatment-refractory tumors

Christoph Grohmann, Francesca Walker, Mark Devlin, Meng-Xiao Luo, Anderly C Chueh, Judy Doherty, Francois Vaillant, Gwo-Yaw Ho, Matthew J Wakefield, Clare E Weeden, Alvin Kamili, Jayne Murray, Sela T Po'uha, Janet Weinstock, Serena R Kane, Maree C Faux, Esmee Broekhuizen, Ye Zheng, Kristy Shield-Artin, Nadia J Kershaw Show all

CELL DEATH & DISEASE | SPRINGERNATURE | Published : 2021

Abstract

Targeting cell division by chemotherapy is a highly effective strategy to treat a wide range of cancers. However, there are limitations of many standard-of-care chemotherapies: undesirable drug toxicity, side-effects, resistance and high cost. New small molecules which kill a wide range of cancer subtypes, with good therapeutic window in vivo, have the potential to complement the current arsenal of anti-cancer agents and deliver improved safety profiles for cancer patients. We describe results with a new anti-cancer small molecule, WEHI-7326, which causes cell cycle arrest in G2/M, cell death in vitro, and displays efficacious anti-tumor activity in vivo. WEHI-7326 induces cell death in a br..

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Grants

Awarded by CRC for Cancer Therapeutics under Australian Government's Cooperative Research Centre scheme, NHMRC from the Australian Government


Awarded by Victorian Cancer agency


Awarded by NHMRC


Awarded by Senior Research Fellowship


Funding Acknowledgements

The authors thank Stephanie Alfred for assistance with drug administration and animal monitoring. We also thank Associate Professor Lenka Munoz for useful discussions. We would like to acknowledge the Australian Ovarian Cancer Study (AOCS) for provision of tumor samples. This research was supported in part by the CRC for Cancer Therapeutics, funded under the Australian Government's Cooperative Research Centre scheme, NHMRC Program Grants #487922, 1113133 from the Australian Government. ML-AL is supported by a Viertel Foundation Senior Medical Researcher Fellowship. CLS is supported by the Stafford Fox Medical Research Foundation, Cancer Council Victoria (Sir Edward Dunlop Fellowship), and the Victorian Cancer agency (CRF1020 and CRF16014). C.E.W. and G.Y.H. are supported by Australian Post-graduate Awards and Cancer Therapeutics CRC top-up scholarships. This work was made possible through grants from the Victorian Cancer Agency, the Harry Secomb Foundation, by the Australian Cancer Research Foundation and by funds from the Operational Infrastructure Support Program provided by the Victorian Government, Australia. Supported by the Australian National Health and Medical Research Council (NHMRC). NHMRC Principal Research Fellowship #APP1119152 (M.K.), NHMRC Senior Principal Research Fellowships #1078730 (G.J.L.), #1037230 (J.E.V.), Senior Research Fellowship #1117089 (G.L.), NHMRC Project Grants #1057805 (G.L., N.J.K., M.K.), #1062702 (C.L.S.). The Centre for Drug Candidate Optimisation is partially supported by the Monash University Technology Research Platform network and Therapeutic Innovation Australia (TIA) through the Australian Government National Collaborative Research Infrastructure Strategy (NCRIS) program. H2B-mScarlet-I plasmid was a gift from the Blewitt laboratory (WEHI).