Abstract The ubiquitin-proteasome system (UPS) is a validated therapeutic target in cancer, as evidenced by the clinical success of proteasome inhibitors. Extensive preclinical studies have further demonstrated that inhibition of the primary mammalian E1 enzyme, ubiquitin-activating enzyme 1 (UBA1), which functions at the apex of the UPS, elicits potent antitumor activity through both tumor-intrinsic and immune-dependent mechanisms. However, the clinical development of the first-in-class UBA1 inhibitor TAK-243 is constrained by its limited patent lifespan, creating a need for next-generation UBA1-targeting agents. Here, we describe NPP-2-21, a novel, rationally engineered small-molecule prodrug designed to selectively inhibit UBA1 with improved pharmacological properties. NPP-2-21 is chemically distinct from previously reported UBA1 inhibitors and is inactive in vitro, but undergoes efficient in vivo conversion to an active UBA1-inhibitory metabolite. This prodrug strategy substantially enhances systemic stability and exposure, resulting in favorable pharmacokinetic and pharmacodynamic profiles and a markedly higher maximum tolerated dose compared with first-generation UBA1 inhibitors, while maintaining high selectivity for UBA1 over other E1 enzymes. Across multiple preclinical tumor models, NPP-2-21 demonstrates superior antitumor efficacy and synergizes with immune checkpoint blockade without inducing systemic toxicity. Notably, NPP-2-21 is compatible with liposomal formulation, enabling a reduction in dosing frequency from six to three doses over two weeks without loss of efficacy or increased toxicity. Collectively, these findings establish NPP-2-21 as a promising translational candidate for UBA1-directed cancer therapy. Citation Format: Yi Bao, Pengpeng Niu, Ke Ding, Arul M. Chinnaiyan. NPP-2-21: A rationally designed prodrug of a UBA1 inhibitor with improved pharmacologic properties and antitumor activity abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB353.
Bao et al. (2026) studied this question.