{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T21:59:54Z","timestamp":1789077594582,"version":"build-2803163510"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T00:00:00Z","timestamp":1717545600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Pacylex Pharmaceuticals Inc."},{"DOI":"10.13039\/501100000001","name":"Alberta Cancer Foundation","doi-asserted-by":"publisher","award":["27369"],"award-info":[{"award-number":["27369"]}],"id":[{"id":"10.13039\/501100000001","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Cure Cancer Foundation \u2018World\u2019s Longest Hockey Game\u2019 and \u2018World\u2019s Longest Baseball Game\u2019"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Invest New Drugs"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Myristoylation, the N-terminal addition of the fatty acid myristate to proteins, regulates membrane-bound signal transduction pathways important in cancer cell biology. This modification is catalyzed by two N-myristoyltransferases, NMT1 and NMT2. Zelenirstat is a first-in-class potent oral small molecule inhibitor of both NMT1 and NMT2 proteins. Patients with advanced solid tumors and relapsed\/refractory (R\/R) B-cell lymphomas were enrolled in an open label, phase I dose escalation trial of oral daily zelenirstat, administered in 28-day cycles until progression or unacceptable toxicity. The endpoints were to evaluate dose-limiting toxicities (DLT) to establish a maximum tolerated dose (MTD), pharmacokinetic parameters, and anticancer activity. Twenty-nine patients were enrolled (25 advanced solid tumor; 4 R\/R B-cell lymphoma) and 24 were DLT-evaluable. Dosing ranged from 20\u00a0mg once daily (OD) to 210\u00a0mg OD without DLT, but gastrointestinal DLTS were seen in the 280\u00a0mg cohort. MTD and recommended phase 2 dose were 210\u00a0mg OD. Common adverse events were predominantly Gr\u2009\u2264\u20092 nausea, vomiting, diarrhea, and fatigue. Plasma concentrations peaked at 2\u00a0h with terminal half-lives averaging 10\u00a0h. Steady state was achieved by day 15, and higher doses achieved trough concentrations predicted to be therapeutic. Stable disease as best response was seen in eight (28%) patients. Progression-free survival and overall survival were significantly better in patients receiving 210\u00a0mg OD compared to those receiving lower doses. Zelenirstat is well-tolerated, achieves plasma exposures expected for efficacy, and shows early signs of anticancer activity. Further clinical development of zelenirstat is warranted.<\/jats:p>","DOI":"10.1007\/s10637-024-01448-w","type":"journal-article","created":{"date-parts":[[2024,6,5]],"date-time":"2024-06-05T11:54:14Z","timestamp":1717588454000},"page":"386-393","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["A first-in-human phase I trial of daily oral zelenirstat, a N-myristoyltransferase inhibitor, in patients with advanced solid tumors and relapsed\/refractory B-cell lymphomas"],"prefix":"10.1007","volume":"42","author":[{"given":"Randeep","family":"Sangha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rahima","family":"Jamal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Spratlin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Kuruvilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie H.","family":"Sehn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Beauchamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Weickert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc G.","family":"Berthiaume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"Mackey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,6,5]]},"reference":[{"key":"1448_CR1","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/s41589-018-0077-5","volume":"14","author":"B Castrec","year":"2018","unstructured":"Castrec B, Dian C, Ciccone S, Ebert CL, Bienvenut WV, Le Caer JP, Steyaert JM, Giglione C, Meinnel T (2018) Structural and genomic decoding of human and plant myristoylomes reveals a definitive recognition pattern. 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M.W. and E.B. are employees of Pacylex Pharmaceuticals Inc. L.G.B., E.B., and J.R.M. own shares in Pacylex Pharmaceuticals Inc. This clinical trial was jointly designed by R.S. and J.R.M. R.S. and J.R.M. shared in the writing of the manuscript and the decision to publish the results.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}