Synergy of FLT3 inhibitors and the small molecule inhibitor of LIM kinase1/2 CEL_Amide in FLT3-ITD mutated Acute Myeloblastic Leukemia (AML) cells

Djamai, Hanane; Berrou, Jeannig; Dupont, Mélanie; Kaci, Anna; Ehlert, Jan E.; Weber, Holger; Baruchel, André; Paublant, Fabrice; Prudent, Renaud; Gardin, Claude; Dombret, Hervé; Braun, Thorsten

doi:10.1016/j.leukres.2020.106490

Cited by 8 publications

(8 citation statements)

References 19 publications

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“…Moreover, in NOD-SCID mice that were engrafted with MOLM13-LUC cells, the FLT3 inhibitor midostaurin, or LIMKi alone, delayed the MOLM13-LUC engraftment, and their combination significantly prolonged the survival of leukemic mice. Taken together, these data suggest that the small molecule inhibitor CEL_Amide LIMKi might constitute a novel treatment strategy for FLT3-ITD+ AML, when used in combination with FLT3 inhibitors [120]. The same group evaluated the efficiency of CEL_Amide LIMKi in Philadelphia chromosome-positive (BCR::ABL+) acute lymphoblastic leukemia (ALL), another subtype of leukaemia.…”

Section: Osteosarcomamentioning

confidence: 98%

LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features

Villalonga

Mosrin

Normand

et al. 2023

Cells

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LIM kinase 1 (LIMK1) and LIM kinase 2 (LIMK2) are serine/threonine and tyrosine kinases and the only two members of the LIM kinase family. They play a crucial role in the regulation of cytoskeleton dynamics by controlling actin filaments and microtubule turnover, especially through the phosphorylation of cofilin, an actin depolymerising factor. Thus, they are involved in many biological processes, such as cell cycle, cell migration, and neuronal differentiation. Consequently, they are also part of numerous pathological mechanisms, especially in cancer, where their involvement has been reported for a few years and has led to the development of a wide range of inhibitors. LIMK1 and LIMK2 are known to be part of the Rho family GTPase signal transduction pathways, but many more partners have been discovered over the decades, and both LIMKs are suspected to be part of an extended and various range of regulation pathways. In this review, we propose to consider the different molecular mechanisms involving LIM kinases and their associated signalling pathways, and to offer a better understanding of their variety of actions within the physiology and physiopathology of the cell.

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Section: Osteosarcomamentioning

confidence: 98%

LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features

Villalonga

Mosrin

Normand

et al. 2023

Cells

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“…In a recent paper, Braun and coworkers investigated the preclinical effects of the LIMK1/2 inhibitor CEL_Amide in FLT3-ITD mutated Acute Myeloid Leukemia cells [67]. The authors targeted LIMKs by using CEL_Amide (LIMKi), a LIMK inhibitor unrelated to the BMS compounds LIMKi3 and LIMKi5.…”

Section: Cel_amidementioning

confidence: 99%

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Berabez

Routier

Bénédetti

et al. 2022

Cells

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LIM Kinases are important actors in the regulation of cytoskeleton dynamics by controlling microtubule and actin filament turnover. The signaling pathways involving LIM kinases for actin filament remodeling are well established. They are downstream effectors of small G proteins of the Rho-GTPases family and have become promising targets for the treatment of several major diseases because of their position at the lower end of these signaling cascades. Cofilin, which depolymerizes actin filaments, is the best-known substrate of these enzymes. The phosphorylation of cofilin to its inactive form by LIM kinases avoids actin filament depolymerization. The balance between phosphorylated and non-phosphorylated cofilin is thought to play an important role in tumor cell invasion and metastasis. Since 2006, many small molecules have been developed for LIMK inhibition, and in this review article, we will discuss the structure–activity relationships of the few inhibitor families that have been tested in vivo on different pathological models.

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“…Despite available targeted drugs, the therapy for FLT3-positive AML remains complicated due to the high rate of resistance to FLT3 inhibitors, often caused by changes in the kinase domain [4]. Various strategies to avoid reduced efficacy of therapy are explored, including combinations with conventional cytotoxics [2] or modern targeted drugs, such as BH3 mimetics [5,6], azacytidine [7], or kinase inhibitors [8][9][10]. Other approaches focus directly on the kinase realm by generating kinase inhibitors targeting resistance-causing FLT3 point mutations [11], or by developing dual targeting compounds, which inhibit FLT3 and another kinase necessary for survival and proliferation of AML cells, for example, JAK2, MEK, MER, or CDK4 [12].…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

Tomanová

Kozlanská

Jorda

et al. 2022

IJMS

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Therapy of FLT3-positive acute myeloid leukemia still remains complicated, despite the availability of newly approved kinase inhibitors. Various strategies to avoid the reduced efficacy of therapy have been explored, including the development of dual targeting compounds, which inhibit FLT3 and another kinase necessary for the survival and proliferation of AML cells. We have designed new 2,7,9-trisubstituted 8-oxopurines as FLT3 inhibitors and report here the structure-activity relationship studies. We demonstrated that substituents at positions 7 and 9 modulate activity between CDK4 and FLT3 kinase, and the isopropyl group at position 7 substantially increased the selectivity toward FLT3 kinase, which led to the discovery of compound 15a (9-cyclopentyl-7-isopropyl-2-((4-(piperazin-1-yl)phenyl)amino)-7,9-dihydro-8H-purin-8-one). Cellular analyses in MV4-11 cells revealed inhibition of autophosphorylation of FLT3 kinase in nanomolar doses, including the suppression of downstream STAT5 and ERK1/2 phosphorylation. We also describe mechanistic studies in cell lines and activity in a mouse xenograft model in vivo.

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Synergy of FLT3 inhibitors and the small molecule inhibitor of LIM kinase1/2 CEL_Amide in FLT3-ITD mutated Acute Myeloblastic Leukemia (AML) cells

Cited by 8 publications

References 19 publications

LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features

LIM Kinases, LIMK1 and LIMK2, Are Crucial Node Actors of the Cell Fate: Molecular to Pathological Features

LIM Kinases, Promising but Reluctant Therapeutic Targets: Chemistry and Preclinical Validation In Vivo

Synthesis and Structural Optimization of 2,7,9-Trisubstituted purin-8-ones as FLT3-ITD Inhibitors

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