Abstract 338: Discovery of novel pan-PI3K and mTOR dual inhibitors as first-in-class antibody-drug conjugate payloads.

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Abstract Despite the clinical success of microtubule inhibitor- and topoisomerase inhibitor-based ADCs, new classes of payloads with alternative mechanisms of action are needed to address clinical resistance and increase tumor responses. Constructing next-generation ADC payloads that target cancer-dependent pathways with a strong biological rationale for combination with other targeted agents, provides an opportunity to develop better-tolerated and more differentiated ADCs. The PI3K/AKT/mTOR signaling pathway is one of the most dysregulated in human cancers. Numerous small molecule efforts have targeted PI3K and mTOR, but these have achieved limited success. These agents are often associated with frequent dose interruptions and discontinuations due to undesirable on-target toxicities, as well as the emergence of drug resistance resulting from AKT reactivation. Here, we present novel pan-PI3K and mTOR dual inhibitors developed as first-in-class ADC payloads. We hypothesize that this novel payload strategy will achieve more robust and durable inhibition of the PI3K/AKT/mTOR pathway. Delivery via an ADC approach is expected to provide meaningful improvements in efficacy and tolerability compared to systemic small molecule treatments. Existing pan-PI3K and mTOR dual inhibitors often lack sufficient potency and present challenges for linker installation to enable an ADC approach. Guided by structure-based design, we have identified novel cores that significantly boost potency against various class I PI3K isoforms and mTOR enzymes, while maintaining excellent selectivity across a broad kinase panel. Additionally, we have explored multiple exit vectors to facilitate ADC linker installation, which is a critical component of ADC development. The resulting PI3Ki/mTORi ADCs exhibited favorable drug-like properties and picomolar potency in cell-killing assays across a range of in vitro tumor models. Importantly, these ADCs also demonstrated a strong bystander effect, attributable to the highly efficient release of the cleavable linker within lysosomes and the permeable nature of the payloads being developed. These ADCs demonstrated significant in vivo efficacy by inducing tumor regressions across a variety of hematological and solid tumor models harboring PI3K genetic alterations, following administration of a single dose ranging from 3 to 10 mg/kg. Moreover, owing to their dual inhibitory activity against both PI3K and mTOR, our ADCs exhibited robust antitumor effects even in models with wild-type PI3K backgrounds, highlighting their broad therapeutic potential. Taken together, the PI3K/mTOR dual-inhibitor modality, combined with an ADC platform, offers an opportunity to target various cancer indications with dependencies on the PI3K/mTOR pathway, and provides opportunities for combination treatment regimens with other anticancer agents. Citation Format: Qi Liu, Lan Pham, Chin Pan, Jin Wang, Kamaldeep S. Dhami, Yingchun Li, Jeffrey Serrill, Ravi Kasiappan, Felix DeAnda, Screenivas Punna, Karl Haelsig, Apeksha Villath, Ketaki Gadkari, Geunbae Rha, Deanna Haasch, Albert Lai, James W. Purcell, Xueqing Wang. Discovery of novel pan-PI3K and mTOR dual inhibitors as first-in-class antibody-drug conjugate payloads [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 338.

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