The anti‐mitotic agents PTC‐028 and PTC596 display potent activity in pre‐clinical models of multiple myeloma but challenge the role of BMI‐1 as an essential tumour gene

Abstract

Summary Future progress in the treatment of multiple myeloma (MM) requires both the characterisation of key drivers of the disease and novel, innovative approaches to tackle these vulnerabilities. The present study focussed on the pre‐clinical evaluation of a novel drug class, BMI‐1 modulators, in MM. We demonstrate potent activity of PTC‐028 and PTC596 in a comprehensive set of in vitro and in vivo models, including models of drug resistance and stromal support. Treatment of MM cells with PTC‐028 and PTC596 downregulated BMI‐1 protein levels, which was found to correlate with drug activity. Surprisingly, BMI‐1 was dispensable for the activity of BMI‐1 modulators and MM cell growth. Our data rather point to mitotic arrest accompanied by myeloid cell leukaemia‐1 (MCL‐1) loss as key anti‐MM mechanisms and reveal impaired MYC and AKT signalling activity due to BMI‐1 modulator treatment. Moreover, we observed a complete eradication of MM after PTC596 treatment in the 5TGM.1 in vivo model and define epigenetic compounds and B cell leukaemia/lymphoma 2 homology domain 3 (BH3) mimetics as promising combination partners. These results bring into question the postulated role of BMI‐1 as an essential MM gene and confirm BMI‐1 modulators as potent anti‐mitotic agents with encouraging pre‐clinical activity that supports their rapid translation into clinical trials.

Pharmacokinetics and Safety of PTC596, a Novel Tubulin‐Binding Agent, in Subjects With Advanced Solid Tumors

“…15 PTC596 has also been investigated for potential treatment of additional BMI1 modulation/expression-related oncology targets, such as pancreatic ductal adenocarcinoma, 16 glioblastoma multiforme, 17 and multiple myeloma. 18 The pharmacokinetics of PTC596 have been investigated in mice, rats, dogs, and monkeys following oral and/or intravenous administrations. Across these species, absolute bioavailability ranged from 14% in dogs to about 79% in rats, with a short half-life of 0.8 to 1.9 hours in dogs and monkeys and a moderate half-life of 4 to 9 hours in mice and rats.…”

Role of Polycomb Complexes in Normal and Malignant Plasma Cells

“…BMI-1 is the most studied PRC1 member and the specificity and effects of several potential inhibitors, such as PTC209 [118,119], PTC596, and PTC028 [120], are currently being investigated in MM. RU-A1 is another potent BMI-1 inhibitor that has not yet been used in MM [121].…”

Efficacy of the novel tubulin polymerization inhibitor PTC‐028 for myelodysplastic syndrome

“…[8][9][10] However, PTC-028 as well as PTC596 exhibited cytotoxic activity independent of BMI1. 7 These findings suggested that PTC-028 also functions as an inhibitor of tubulin assembly.…”

“…PTC596 was recently identified as a direct microtubule polymerization inhibitor in a preclinical study on pancreatic ductal adenocarcinoma and its function as a BMI1 modulator was shown to be a secondary effect 4 . PTC596 induces cytotoxicity in various tumor cell lines and exerts preclinical effects on hematological malignancies, such as AML, mantle cell leukemia, and multiple myeloma 5‐7 . Clinical trials on PTC596 are ongoing for diffuse intrinsic pontine glioma, leiomyosarcoma, and ovarian cancer (ClinicalTrials.gov identifiers: NCT03605550, NCT03761095, and NCT03206645).…”

“…BMI1 protein is a component of polycomb repressive complex 1 that maintains the transcriptional repression of target genes via ubiquityl histone H2A. [5][6][7] was recently identified as a direct microtubule polymerization inhibitor in a preclinical study on pancreatic ductal adenocarcinoma and its function as a BMI1 modulator was shown to be a secondary effect. 4 PTC596 induces cytotoxicity in various tumor cell lines and exerts preclinical effects on hematological malignancies, such as AML, mantle cell leukemia, and multiple myeloma.…”