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Abstract Background: Relapsed/refractory (R/R) AML remains an area of high unmet need despite recent therapeutic advances. Zelenirstat (PCLX-001) is an orally bioavailable, first-in-class inhibitor of both human N-myristoyltransferases (NMT1 and NMT2), inhibiting Src-family kinase cell signaling and mitochondrial oxidative phosphorylation. Zelenirstat potently suppresses AML cell growth and leukemic stem-cell survival in pre-clinical models. A completed first-in-human study in lymphoma and solid tumors showed continuous target-inhibitory plasma concentrations without dose-limiting toxicities up to 210 mg once daily, providing a strong rationale for evaluation in AML patients. Additionally, Zelenirstat has shown profound synergy with venetoclax in preclinical models of AML (doi www.10.1158/1535-7163.MCT-24-0307 ). Study design and methods: This single-center, open-label, dose-finding trial is being conducted at MD Anderson Cancer Center. Part A employs a Bayesian Optimal Interval design to identify the minimum safe and biologically effective dose (MSBED) across ≤15 patients; Part B enrolls 20 additional evaluable patients at the MSBED for preliminary safety and activity assessment. Zelenirstat is administered orally once daily in 28-day cycles with continuous azole prophylaxis. Key eligibility criteria include adults ≥18 years with R/R AML after ≥1 prior therapy, ECOG 0-2, and adequate hepatic, renal, and cardiac function. Objectives: Primary—(i) evaluate safety and tolerability; (ii) determine the MSBED; (iii) characterize Zelenirstat pharmacokinetics in the presence of CYP3A inhibitors. Secondary—estimate overall response rate (ORR), duration of response, event-free survival, and overall survival in the expansion cohort. Exploratory—correlate NMT1/2 expression and pharmacodynamic biomarkers (e.g., Lyn, Src, HGAL) with clinical outcomes. Statistical considerations: BOIN rules guide escalation decisions; simultaneous Bayesian monitoring of best response and toxicity governs expansion futility and safety thresholds. Descriptive statistics and 95% credible intervals will be used for clinical endpoints; no formal hypothesis testing is planned. Sample size (≤35) affords an estimated 95% credible interval of 0.07-0.39 if 4/20 responses are observed in expansion. Current status: First-patient/first-visit (FPFV) was in Q1 2025, and enrollment is ongoing in early stages. Recruitment updates and any protocol amendments will be presented in the poster. Trial registration: ClinicalTrials.gov identifier NCT06613217. Conclusion: This TiP abstract summarizes the rationale and design of the first study of Zelenirstat in R/R AML. The trial will inform the safety profile, biologically effective dosing, and early signals of activity of NMT inhibition in AML and lay the groundwork for future combination strategies with venetoclax and other synergistic drugs.