Development of novel anti-cancer drug by “locking inhibition” of amino acid transporter LAT1.

Abstract

e15105 Background: Large Amino Acid Transporter 1 (LAT1) is critical for transporting essential amino acids, enabling the growth and proliferation of cancer cells. LAT1 is overexpressed via oncogene Myc-pathway in aggressive tumors, making it a promising therapeutic target. LAT1 inhibition disrupts mTORC1 pathway and the metabolic programs, vital for cancer progression. To address the limitations of currently developed reversible inhibitors, we developed APL1101, a first-in-class LAT1 inhibitor that achieves an effectively irreversible, noncovalent “locking” mechanism to durably block amino acid transport. Methods: Preclinical efficacy studies of APL1101 involved in vitro and in vivo models, including LAT1-overexpressing xenograft tumors such as non-small cell lung cancer and triple-negative breast cancer. Toxicity, and pharmacokinetics (PK) were evaluated in rodents and canines to assess safety, drug distribution, and LAT1 occupancy. Combination studies were also performed to explore synergy with existing therapies. Results: APL1101 demonstrated potent and selective LAT1 inhibition in vitro (Ki < 20 nM), significantly reducing tumor cell proliferation. In vivo, it achieved more than 70% tumor growth suppression in xenograft models without causing systemic toxicity or weight loss. PK studies revealed sufficient Cmax and a long half-life, supporting sustained efficacy. Toxicology studies in rodents and canines confirmed a favorable safety profile, with no off-target effects and high tolerability. Notably, preclinical data suggest that combining APL1101 with immune checkpoint inhibitors or standard chemotherapy agents can synergistically enhance anti-tumor efficacy. Clinical Development: Preparations for a Phase 1/2a clinical trial are underway, with Phase 1 scheduled to begin in Q4 2026. The trial will evaluate safety, tolerability, and efficacy in patients with advanced solid tumors. Phase 2a will focus on LAT1-overexpressing cancers using biomarker-driven stratification. APL1101’s mechanism of action, targeting mTORC1 pathway and metabolic programs, underscores its broader potential across multiple solid and hematologic malignancies. Conclusions: APL1101’s innovative irreversible LAT1 inhibition mechanism demonstrates robust preclinical efficacy and safety, supporting its potential as a transformative therapy for aggressive cancers. Its versatility as a monotherapy or in combination regimens with chemotherapeutics and immunotherapies offers significant promise for broader cancer treatment. The upcoming clinical trials will provide critical insights into its full therapeutic potential.