ADN‑388 is a newly synthesized small‑molecule antagonist designed to disrupt the programmed death‑1 (PD‑1)/programmed death‑ligand 1 (PD‑L1) protein‑protein interaction that underlies tumor‑mediated immune evasion. Here we present a comprehensive pre‑clinical dossier encompassing (i) rational design and physicochemical profiling, (ii) in‑vitro binding affinity and functional blockade assays, (iii) cellular pharmacology in human peripheral blood mononuclear cells (PBMCs) and tumor‑derived co‑culture systems, (iv) pharmacokinetics (PK) and safety in two rodent species, and (v) efficacy in three syngeneic murine tumor models. ADN‑388 displayed sub‑nanomolar binding (K D = 0.42 nM), potent restoration of T‑cell activation (EC 50 = 8 nM), favorable oral bioavailability (F ≈ 45 % in rats), and a clean toxicity profile (no observed adverse effect level, NOAEL = 150 mg kg⁻¹ day⁻¹). In vivo, oral administration (30 mg kg⁻¹ qd) produced tumor growth inhibition (TGI) of 73 % in MC38 colon carcinoma, 68 % in B16‑F10 melanoma, and 61 % in 4T1 breast carcinoma, with synergistic benefit when combined with low‑dose cyclophosphamide. These data support ADN‑388 as a promising oral immuno‑oncology candidate warranting IND‑enabling studies.
Preclinical studies have demonstrated the efficacy and safety of ADN-388 in models of various cancers, including NSCLC, gastric cancer, and pancreatic cancer. In these studies, ADN-388 exhibited potent anti-tumor activity, inhibiting tumor growth and extension in animal models. Additionally, ADN-388 was well-tolerated, with minimal toxicity and side effects observed. adn-388