Orally available tubulin inhibitor VERU-111 enhances antitumor efficacy in paclitaxel-resistant lung cancer

The Tubulin Inhibitor VERU-111 in Combination With Vemurafenib Provides an Effective Treatment of Vemurafenib-Resistant A375 Melanoma

“…A375 cells are one of the most widely used and representative V600E mutant melanoma cells, and we have previously reported the anti-tumor efficiency of VERU-111 in many cancer types ( Kashyap et al, 2019 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ) as well as the synergy of Vem in combination with ABI-274 in A375 Vem-resistant melanoma cells ( Wang et al, 2014 ). Herein, we investigate whether the combination of VERU-111 (ABI-274 derivative) with Vem can also overcome Vem-resistance in A375.…”

“…VERU-111 (ABI-231) is an orally available tubulin inhibitor that disrupts tubulin polymerization, promotes microtubule fragmentation, inhibits cancer cell migration, and is currently in phase 1b/2 clinical trials for men with metastatic castration and androgen-blocking agent resistant prostate cancer ( ClinicalTrials.gov Identifier: NCT03752099). Tubulin inhibitor is less prone to develop resistance, therefore bearing potential to cure cancer and to sensitize drug-resistance cancer patience ( Wang et al, 2014 ; Guan et al, 2017 ; Arnst et al, 2018 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ).…”

“…Although combinations of BRAF inhibitor with MEK or ERK inhibitors benefit Vem-resistant patients ( Atefi et al, 2011 ; Gadiot et al, 2013 ; Pulkkinen et al, 2020 ), half of the patients still gain resistance after 6–8 months. Intriguingly, some tubulin destabilizing agents reported previously by us targeting the colchicine-binding site showed promise to overcome Vem-resistance, paclitaxel-resistance in melanoma, breast cancer, lung cancer, prostate cancer, cervical cancer et al ( Wang et al, 2014 ; Guan et al, 2017 ; Arnst et al, 2018 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ). In our previous studies, we have demonstrated that a tool tubulin inhibitor, ABI-274, showed strong synergistic efficacy in a Vem-resistant xenograft mouse model ( Wang et al, 2014 ).…”

“…ABI-274 is a tool compound developed in our lab as a potent tubulin inhibitor that binds to the colchicine binding site (Chen et al, 2010;Wang et al, 2018). Further structural optimization from ABI-274 led to VERU-111 (Figure 1A), which is orally available and much more potent and less toxic in several types of tumor models, including prostate cancer, melanoma, breast cancer, lung cancer, and pancreatic cancer (Chen et al, 2012;Deng et al, 2020;Kashyap et al, 2020;Mahmud et al, 2020 (Chen et al, 2020). VERU-111 has now been under Phase 1b/2 clinical trials for men with metastatic castration and androgen-blocking agent resistant prostate cancer (ClinicalTrials.gov Identifier: NCT03752099) and holds great promise to become an oral tubulin inhibitor targeting the colchicine binding site.…”

“…ABI-274 is a tool compound developed in our lab as a potent tubulin inhibitor that binds to the colchicine binding site ( Chen et al, 2010 ; Wang et al, 2018 ). Further structural optimization from ABI-274 led to VERU-111 ( Figure 1A ), which is orally available and much more potent and less toxic in several types of tumor models, including prostate cancer, melanoma, breast cancer, lung cancer, and pancreatic cancer ( Chen et al, 2012 ; Deng et al, 2020 ; Kashyap et al, 2020 ; Mahmud et al, 2020 ). As literature reported, the IC 50 of ABI-274 was 25.3 nM while IC 50 of VERU-111 was 8.2 nM in MDA-MB-231 breast cancer cell, and the IC 50 of ABI-274 was 18.7 nM while IC 50 of VERU-111 was 10.4 nM in A375 melanoma cell ( Chen et al, 2020 ).…”