• Crenolanib displays activity against several of the important kinase domain mutations (at position D835) found in FLT3.• Patients receiving crenolanib achieve FLT3-inhibitory plasma levels.Mutations of the type III receptor tyrosine kinase FLT3 occur in approximately 30% of acute myeloid leukemia patients and lead to constitutive activation. This has made FLT3-activating mutations an attractive drug target because they are probable driver mutations of this disease. As more potent FLT3 inhibitors are developed, a predictable development of resistance-conferring point mutations, commonly at residue D835, has been observed. Crenolanib is a highly selective and potent FLT3 tyrosine kinase inhibitor (TKI) with activity against the internal tandem duplication (FLT3/ITD) mutants and the FLT3/D835 point mutants. We tested crenolanib against a panel of D835 mutant cell lines and primary patient blasts and observed superior cytotoxic effects when compared with other available FLT3 TKIs such as quizartinib and sorafenib. Another potential advantage of crenolanib is its reduced inhibition of c-Kit compared with quizartinib. In progenitor cell assays, crenolanib was less disruptive of erythroid colony growth, which may result in relatively less myelosuppression than quizartinib. Finally, correlative data from an ongoing clinical trial demonstrate that acute myeloid leukemia patients can achieve sufficient levels of crenolanib to inhibit both FLT3/ITD and resistance-conferring FLT3/D835 mutants in vivo. Crenolanib is thus an important next-generation FLT3 TKI. This study is registered at clinicaltrials.gov (ID: NCT01657682). (Blood. 2014;123(1):94-100)
Several small molecule tyrosine kinase inhibitors (TKIs) inhibit c-Kit, an effect associated with myelosuppression and hair depigmentation. We studied a panel of approved and investigational TKIs for inhibitory activity against FLT3 and c-Kit, and on hematopoietic progenitor cells. Potent cKit inhibitors such as dasatinib, pazopanib, and quizartinib demonstrated the greatest disruption of hematopoietic progenitor cells, while sorafenib, which has negligible activity against c-Kit, demonstrated only minimal disruption. Our data highlight the importance of determining a therapeutic index between the targeted receptor and c-Kit for TKIs used to treat malignancies in order to maintain normal hematopoiesis and improve outcomes.Myelosuppression is a common adverse event in new drug development in oncology. Many tyrosine kinase inhibitors (TKIs) have activity against c-Kit, a receptor tyrosine kinase (RTK) which is essential for normal hematopoiesis.1 The c-Kit receptor is an important marker of long-term hematopoietic stem cells, and it also plays an important role in hair and skin pigmentation. For example, the W mouse, in which the function of c-Kit is impaired, has white spots, anemia, and reduced megakorycytes, and c-Kit knockouts in transgenic mice is embryonic lethal (reviewed by Lyman and Jacobsen 1). Patients treated with TKIs that inhibit c-Kit, therefore, are at risk for myelosuppression.2 In vivo c-Kit inhibition is also associated with hair depigmentation ( Figure 1A).3 Drugs such as pazopanib and sunitinib, which have activity against c-Kit, do not induce myelosuppression in solid tumor patients when used as single agents. In contrast, dasatinib and imatinib, which also inhibit c-Kit, have been associated with myelosuppression in patients with Philadelphia-positive (Ph + ) leukemia. 4In patients with relapsed/refractory FLT3/ITD acute myeloid leukemia (AML), treatment with the FLT3 inhibitor quizartinib was associated with myelosuppression, whereas in a similar patient population, a different FLT3 inhibitor, sorafenib, induced no myelosuppression. 5,6To better understand the relationship between inhibition of c-Kit, FLT3, and marrow suppression, we studied a series of different TKIs using bone marrow progenitor cell assays and immunoblots.Cell lines were cultured as previously described. 2 TF-1 cells were obtained from the American Type Culture Collection (ATCC; Manassas, VA, USA) and grown in RPMI supplemented with GM-CSF (Invitrogen, Grand Island, NY, USA). Quizartinib was obtained from Ambit Biosciences (San Diego, CA, USA). Crenolanib was obtained from Arog Pharmaceuticals (Dallas, TX, USA). Dasatinib, pazopanib, and imatinib were obtained from LC Laboratories (Woburn, MA, USA). Electrophoresis, immunoblotting, and hematopoietic progenitor cell assays were performed as described. 2Cytokines used included SCF, G-CSF, GM-CSF, IL-3, IL-6, and erythropoietin. Unused portions of bone marrow from normal donors were collected under an institutional review boardapproved Tumor and Cell Procurement Bank at John...
There have been a number of clinical trials testing the efficacy of FLT3 tyrosine kinase inhibitors (TKIs) in acute myeloid leukemia (AML). patients harboring a constitutively activating mutation in FLT3 However, there has been limited efficacy, most often due to inadequate achievement of FLT3 inhibition through a variety of mechanisms In a previous study, TTT-3002 was identified as a novel FLT3 inhibitor with the most potent activity to date against FLT3 internal tandem duplication (FLT3/ITD) mutations Here the activity of TTT-3002 is demonstrated against a broad spectrum of FLT3 activating point mutations (FLT3/PMs), including the most frequently occurring D835 mutations The compound is also active against a number of point mutations selected for in FLT3/ITD alleles that confer resistance to other TKIs, including the F691L gatekeeper mutation TTT-3002 maintains activity against relapsed AML patient samples that are resistant to sorafenib and AC220 Studies utilizing human plasma samples from healthy donors and AML patients indicate that TTT-3002 is only moderately protein bound compared to several other TKIs currently in clinical trials Tumor burden of mice in a FLT3 TKI-resistant transplant model is significantly improved by oral dosing of TTT-3002 Therefore, TTT-3002 has demonstrated preclinical potential as a promising new FLT3 TKI that may overcome some of the limitations of other TKIs in the treatment of FLT3-mutant AML
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.