Preclinical evaluation of the selective small-molecule UBA1 inhibitor, TAK-243, in acute myeloid leukemia

Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy for which new therapeutic approaches are required. One such potential therapeutic strategy is to target the ubiquitin-like modifier-activating enzyme 1 (UBA1), the initiating enzyme in the ubiquitylation cascade in which proteins are tagged with ubiquitin moieties to regulate their degradation or function. Here, we evaluated TAK-243, a first-in-class UBA1 inhibitor, in preclinical models of AML. In AML cell lines and primary AML samples, TAK-243 induced cell death and inhibited clonogenic growth. In contrast, normal hematopoietic progenitor cells were more resistant. TAK-243 preferentially bound to UBA1 over the related E1 enzymes UBA2, UBA3, and UBA6 in intact AML cells. Inhibition of UBA1 with TAK-243 decreased levels of ubiquitylated proteins, increased markers of proteotoxic stress and DNA damage stress. In vivo, TAK-243 reduced leukemic burden and targeted leukemic stem cells without evidence of toxicity. Finally, we selected populations of AML cells resistant to TAK-243 and identified missense mutations in the adenylation domain of UBA1. Thus, our data demonstrate that TAK-243 targets AML cells and stem cells and support a clinical trial of TAK-243 in this patient population. Moreover, we provide insight into potential mechanisms of acquired resistance to UBA1 inhibitors.

Ubiquitin activation is essential for schizont maturation in Plasmodium falciparum blood-stage development

“…The evolution of parasite resistance to such inhibitors is also an important concern that should be address early in the drug discovery process [ 26 ]. A previous study showed that upon MLN7243 treatment HsUBA1 Ala580, which has been designated as the gatekeeper residue, is replaced with a serine [ 55 ], thereby providing drug resistance. PfUBA1 has an alanine at this position (Ala633) and hence drug resistance to adenosyl sulfamates might develop in P .…”

The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

“…Recently, we evaluated a first-in-class small-molecule UBA1 inhibitor developed by Takeda Pharmaceuticals, TAK-243, in preclinical models of AML [4]. TAK-243 is an adenosine sulphamate related to pevonedistat, a NEDD8-activating enzyme (NAE) inhibitor and the prototype of this class of mechanism-based E1 inhibitors [5].…”

The deubiquitinase (DUB) USP13 promotes Mcl-1 stabilisation in cervical cancer

“…As such, targeting the enzymes responsible for either the addition or removal of ubiquitin offers a potential therapeutic avenue. Encouragingly, a number of small molecule inhibitors of ubiquitin-associated enzymes are currently entering pre-clinical trials (51)(52)(53)(54)(55). Here, we screened the TCGA cervical cancer database for the expression of DUBs, enzymes which catalyse the remove of ubiquitin from protein substrates (5).…”