Journal Article

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

Visvader, Jane E., Fletcher, Jamie I., Doherty, Judy, Charman, Susan A., Kershaw, Nadia J., Witchard, Helen M., Haber, Michelle, Broekhuizen, Esmee, Ebert, Gregor, Ho, Gwo-Yaw, Lessene, Guillaume, Chüeh, Anderly C., Weinstock, Janet, Po’uha, Sela T., Zheng, Ye, Faux, Maree C., Lindeman, Geoffrey J., Grohmann, Christoph, Wakefield, Matthew J., Murray, Jayne, Weeden, Clare E., Kamili, Alvin, Kane, Serena R., Walker, Francesca, Shield-Artin, Kristy, Devlin, Mark, Watson, Keith G., Burgess, Antony W., Tan, Chin Wee, Asselin-Labat, Marie-Liesse, Scott, Clare L., Luo, Meng-Xiao, Kavallaris, Maria, Vaillant, François, Street, Ian

2021

Overview

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 broad range of cancer cell lines, including taxane-resistant cells, and inhibits growth of human colon, brain, lung, prostate and breast tumors in mice xenografts. Importantly, the compound elicits tumor responses as a single agent in patient-derived xenografts of clinically aggressive, treatment-refractory neuroblastoma, breast, lung and ovarian cancer. In combination with standard-of-care, WEHI-7326 induces a remarkable complete response in a mouse model of high-risk neuroblastoma. WEHI-7326 is mechanistically distinct from known microtubule-targeting agents and blocks cells early in mitosis to inhibit cell division, ultimately leading to apoptotic cell death. The compound is simple to produce and possesses favorable pharmacokinetic and toxicity profiles in rodents. It represents a novel class of anti-cancer therapeutics with excellent potential for further development due to the ease of synthesis, simple formulation, moderate side effects and potent in vivo activity. WEHI-7326 has the potential to complement current frontline anti-cancer drugs and to overcome drug resistance in a wide range of cancers.

• Publisher: Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/31 / 14/19 / 14/34 / 14/5 / 14/63 / 631/67/1059/153 / 631/67/1059/2326 / 631/67/1347 / 631/67/70 / 631/80/641/1655 / 64/110 / 64/60 / 82/29 / Animal models / Animals / Antibodies / Antimitotic Agents - pharmacokinetics / Antimitotic Agents - pharmacology / Antimitotic Agents - toxicity / Antitumor agents / Apoptosis / Apoptosis - drug effects / Biochemistry / Biomedical and Life Sciences / Breast cancer / Cancer / Cell Biology / Cell Culture / Cell cycle / Cell death / Cell division / Cell Proliferation - drug effects / Chemotherapy / Colon / Drug resistance / Drug Resistance, Neoplasm / Female / G2 Phase Cell Cycle Checkpoints - drug effects / Hep G2 Cells / Humans / Immunology / Life Sciences / Lung cancer / Mice / Mice, Inbred BALB C / Mice, Inbred C57BL / Mice, Nude / Mitosis / Mitosis - drug effects / Neoplasms - drug therapy / Neoplasms - pathology / Neuroblastoma / Ovarian cancer / PC-3 Cells / Pharmacokinetics / Prostate / Rats / Rats, Sprague-Dawley / Side effects / Toxicity / Tumor Burden - drug effects / Tumor cell lines / Tumors / Xenograft Model Antitumor Assays / Xenografts