Evaluation and critical assessment of putative MCL-1 inhibitors

Abstract

High levels of BCL-2 family proteins are implicated in a failed/ineffective apoptotic programme, often resulting in diseases, including cancer. Owing to their potential as drug targets in cancer therapy, several inhibitors of BCL-2 family proteins have been developed. These primarily target specific members of the BCL-2 family, particularly BCL-2 and BCL-X L but are ineffective against MCL-1. Major efforts have been invested in developing inhibitors of MCL-1, which is commonly amplified in human tumours and associated with tumour relapse and chemoresistance. In this report, the specificity of several BCL-2 family inhibitors (ABT-263, UCB-1350883, apogossypol and BH3I-1) was investigated and compared with putative MCL-1 inhibitors designed to exhibit improved or selective binding affinities for MCL-1 (TW-37, BI97C1, BI97C10, BI112D1, compounds 6 and 7, and MCL-1 inhibitor molecule (MIM-1)). ABT-263, BI97C1, BI112D1, MIM-1 and TW-37 exhibited specificity in inducing apoptosis in a Bax/Bak-and caspase-9-dependent manner, whereas the other agents showed no killing activity, or little or no specificity. Of these inhibitors, only ABT-263 and UCB-1350883 induced apoptosis in a BCL-2-or BCL-X L -dependent system. In cells that depend on MCL-1 for survival, ABT-263 and TW-37 induced extensive apoptosis, suggesting that at high concentrations these inhibitors have the propensity to inhibit MCL-1 in a cellular context. TW-37 induced apoptosis, assessed by chromatin condensation, caspase processing and phosphatidylserine externalisation, in a BAK-dependent manner and in cells that require MCL-1 for survival. TW-37-mediated apoptosis was also partly dependent on NOXA, suggesting that derivatives of TW-37, if engineered to exhibit better selectivity and efficacy at low nanomolar concentrations, may provide useful lead compounds for further synthetic programmes. Expanded medicinal chemistry iteration, as performed for the ABT series, may likewise improve the potency and specificity of the evaluated MCL-1 inhibitors.

Seeking a MCL-1 inhibitor

“…In this issue of Cell Death and Differentiation, Varadarajan and colleagues 5 have put to the test a range of lead compounds that may have some claim to MCL-1 specificity. In designing their experiments, they have considered just what might characterize a specific MCL-1 inhibitor.…”

BH3 mimetics: Their action and efficacy in cancer chemotherapy

“…BI97C1 (sabutoclax) [62] BCL-2, BCL-XL, BCL-2A1, MCL-1 BI97C1 induce apoptosis in culture cells in a BAX/BAK-and caspase-9-dependent manner [63].…”

“…BI97C1 was able to block c-Met activation, a critical axis in PCa metastatic progression [64]. TW-37 were more effective than ABT-263 and also resulted in BAX/ BAK-and caspase-9-dependent apoptosis [63]. However, such specificity was generally lost when TW-37 was used at high concentrations (>10 µM), possibly because of off-target effects [63].…”

“…MIM1 induced BAK-dependent apoptosis only at high concentrations (>10 µM) and failed to induce apoptosis in MCL-1-, BCL-2-and BCL-XL-dependent cell lines. Its potency may be limited and cell-typedependent [63].…”

“…Neither compound killed Jurkat cells, even at high concentrations (<30nM), as a single agent or in combination with ABT-737 [63].…”