{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T05:15:54Z","timestamp":1790745354061,"version":"4.1.0"},"reference-count":24,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T00:00:00Z","timestamp":1668470400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CELLIPSE Company"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Ph+ (BCR::ABL+) B-ALL was considered to be high risk, but recent advances in BCR::ABL-targeting TKIs has shown improved outcomes in combination with backbone chemotherapy. Nevertheless, new treatment strategies are needed, including approaches without chemotherapy for elderly patients. LIMK1\/2 acts downstream from various signaling pathways, which modifies cytoskeleton dynamics via phosphorylation of cofilin. Upstream of LIMK1\/2, ROCK is constitutively activated by BCR::ABL, and upon activation, ROCK leads to the phosphorylation of LIMK1\/2, resulting in the inactivation of cofilin by its phosphorylation and subsequently abrogating its apoptosis-promoting activity. Here, we demonstrate the anti-leukemic effects of a novel LIMK1\/2 inhibitor (LIMKi) CEL_Amide in vitro and in vivo for BCR::ABL-driven B-ALL. The IC50 value of CEL_Amide was \u22641000 nM in BCR::ABL+ TOM-1 and BV-173 cells and induced dose-dependent apoptosis and cell cycle arrest in these cell lines. LIMK1\/2 were expressed in BCR::ABL+ cell lines and patient cells and LIMKi treatment decreased LIMK1 protein expression, whereas LIMK2 expression was unaffected. As expected, CEL_Amide exposure caused specific activating downstream dephosphorylation of cofilin in cell lines and primary cells. Combination experiments with CEL_Amide and BCR::ABL TKIs imatinib, dasatinib, nilotinib, and ponatinib were synergistic for the treatment of both TOM-1 and BV-173 cells. CDKN2Ako\/BCR::ABL1+ B-ALL cells were transplanted in mice, which were treated with combinations of CEL_Amide and nilotinib or ponatinib, which significantly prolonged their survival. Altogether, the LIMKi CEL_Amide yields activity in Ph+ ALL models when combined with BCR::ABL-targeting TKIs, showing promising synergy that warrants further investigation.<\/jats:p>","DOI":"10.3390\/jcm11226761","type":"journal-article","created":{"date-parts":[[2022,11,16]],"date-time":"2022-11-16T02:36:36Z","timestamp":1668566196000},"page":"6761","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Preclinical Evaluation of a Novel Small Molecule Inhibitor of LIM Kinases (LIMK) CEL_Amide in Philadelphia-Chromosome Positive (BCR::ABL+) Acute Lymphoblastic Leukemia (ALL)"],"prefix":"10.3390","volume":"11","author":[{"given":"Jeannig","family":"Berrou","sequence":"first","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e9lanie","family":"Dupont","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanane","family":"Djamai","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Adic\u00e9am","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00e9ronique","family":"Parietti","sequence":"additional","affiliation":[{"name":"INSERM\/CNRS, US53\/UAR2030, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Kaci","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7098-092X","authenticated-orcid":false,"given":"Emmanuelle","family":"Clappier","sequence":"additional","affiliation":[{"name":"Laboratory of Hematology, H\u00f4pital Saint-Louis (Assistance Publique\u2013H\u00f4pitaux de Paris and Universit\u00e9 Paris Cit\u00e9), 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Cayuela","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"},{"name":"Laboratory of Hematology, H\u00f4pital Saint-Louis (Assistance Publique\u2013H\u00f4pitaux de Paris and Universit\u00e9 Paris Cit\u00e9), 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9","family":"Baruchel","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"},{"name":"Department of Pediatric Hemato-Immunology, H\u00f4pital Universitaire Robert Debr\u00e9 (Assistance Publique\u2013H\u00f4pitaux de Paris and Universit\u00e9 Paris Cit\u00e9), 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabrice","family":"Paublant","sequence":"additional","affiliation":[{"name":"CELLIPSE Company, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renaud","family":"Prudent","sequence":"additional","affiliation":[{"name":"CELLIPSE Company, 38000 Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Ghysdael","sequence":"additional","affiliation":[{"name":"CNRS UMR3348, INSERM U1278, Institut Curie, Centre Universitaire Bat 110, 91405 Orsay, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Gardin","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"},{"name":"Hematology Department, H\u00f4pital Avicenne (Assistance Publique\u2013H\u00f4pitaux de Paris and Universit\u00e9 Paris XIII), 93000 Bobigny, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herv\u00e9","family":"Dombret","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"},{"name":"Leukemia Unit, Hematology Department, H\u00f4pital Saint-Louis (Assistance Publique\u2013H\u00f4pitaux de Paris and Universit\u00e9 Paris Cit\u00e9), 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten","family":"Braun","sequence":"additional","affiliation":[{"name":"Laboratoire de Transfert des Leuc\u00e9mies, URP-3518, Institut de Recherche Saint-Louis, Universit\u00e9 Paris Cit\u00e9, 75010 Paris, France"},{"name":"Hematology Department, H\u00f4pital Avicenne (Assistance Publique\u2013H\u00f4pitaux de Paris and Universit\u00e9 Paris XIII), 93000 Bobigny, 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