A first-in-human, phase 1 study of the NEDD8 activating enzyme E1 inhibitor TAS4464 in patients with advanced solid tumors

Abstract

SummaryBackground This open-label, phase 1 study investigated TAS4464, a potent NEDD8-activating enzyme inhibitor, in patients with advanced/metastatic solid tumors (JapicCTI-173,488; registered 13/01/2017). The primary objective was dose-limiting toxicities (DLTs). Maximum-tolerated dose (MTD) was investigated using an accelerated titration design. Methods The starting 10-mg/m2 dose was followed by an initial accelerated stage (weekly dosing; n = 11). Based on liver function test (LFT) results, a 14-day, 20-mg/m2 dose lead-in period was implemented (weekly dosing with lead-in; n = 6). Results Abnormal LFT changes and gastrointestinal effects were the most common treatment-related adverse events (AEs). DLTs with 56-mg/m2 weekly dosing occurred in 1/5 patients; five patients had grade ≥ 2 abnormal LFT changes at 40- and 56-mg/m2 weekly doses. Further dose escalation ceased because of the possibility of severe abnormal LFT changes occurring. DLTs with weekly dosing with lead-in occurred in 1/5 patients at a 56-mg/m2 dose; MTD could not be determined because discontinuation criteria for additional enrollment at that particular dose level were met. As no further enrollment at lower doses occurred, dose escalation assessment was discontinued. Serious treatment-related AEs, AEs leading to treatment discontinuation, and DLTs were all related to abnormal LFT changes, suggesting that TAS4464 administration could affect liver function. This effect was dose-dependent but considered reversible. Complete or partial responses to TAS4464 were not observed; one patient achieved prolonged stable disease. Conclusions MTD could not be determined due to TAS4464 effects on liver function. Further evaluation of the mechanism of NEDD8-activating enzyme inhibitor-induced abnormal liver function is required. Trial registration number JapicCTI-173,488 (registered with Japan Pharmaceutical Information Center). Registration date 13 January 2017

Precision Oncology with Drugs Targeting the Replication Stress, ATR, and Schlafen 11

“…The degradation of CDK inhibitors such as p27, p21, and p57 during cell cycle transition is also controlled by CRL E3 ubiquitin ligase complexes, sug-gesting that the ubiquitin pathways can be a promising target for cancer treatment [88]. Two small molecules, pevonedistat (TAK-924/MLN4924) and TAS4464, are in clinical trials [89,90]. They suppress the activity of the NEDD8-activating enzyme, interfering with NEDD8 conjugation (neddylation) that activates CRLs as a key post-translational modification [91].…”

SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy

“…NAE inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies [43] . However, stand-alone clinical trials of these inhibitors have been unsuccessful, due to insufficient clinical benefits and difficulty in defining suitable patient populations [44] . Compared with MLN4924, SOMCL-19-133 has enhanced antitumor activity resulting from increased blockage of neddylation modification.…”

A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer

“… 17 The most significant one, TAS4464, 33 – 35 has completed the phase I clinical trial recently in patients with advanced solid tumors but discontinued due to liver toxicity. 36 Quite a few small molecular inhibitors targeting DCN1-UBE2M/UBC12 interaction have also been reported (for review, see ref. 37 ), including a recent one that protects mice from liver toxicity induced by acetaminophen.…”