Weisberg calcusyn
Oral dosing of G-749 leads to complete tumor regression without relapse in the mouse xenograft model and increases survival in the bone marrow engraftment model. Notably, in comparison with PKC412 and AC220, G-749 shows several desirable characteristics to overcome other known drug resistances conferred by patient plasma, FL surge, and protection by stromal cells.
Using BaF3 model cells, we demonstrate that G-749 is highly potent against clinically known FLT3 mutants including gatekeeper and TKD that confer resistance to PKC412 and AC220. Here, we report that a novel inhibitor, G-749, with a unique kinase inhibition profile is very potent against FLT3 kinase and provides sustained inhibition of FLT3 phosphorylation and downstream effectors in FLT3-ITD–expressing cell lines. 27 Therefore, there is an unmet need for the next-generation FLT3 inhibitor to overcome drug resistance. 22-26 The increased secretion of FL after induction therapy of cytarabine was also known to attenuate efficacy of FLT3 inhibitors. It was shown that bone marrow stromal cells support the survival of neighboring blast cells, resulting in the long-term survival and growth of leukemia cells. 21 The bone marrow microenvironment also contributes to the reduction of drug sensitivity in vivo. 20 Drug resistance comes from PIA where the inhibition of PKC412 and CEP701 against FLT3 autophosphorylation was dramatically decreased in human plasma milieu. 16, 19 Additional resistance mutations to AC220 have also been described using in vitro models. Point mutations within the kinase domain of FLT3-ITD especially at the positions of N676, F691, and D835 lead to substantial resistance to AC220 and PKC412. 16-18 Various factors including point mutations, plasma inhibitory activity (PIA), protective effect by bone marrow stromal cells, and high levels of FLT3 ligand (FL) have been identified to confer FLT3 inhibitor drug resistance.
Recent evidence suggests that the majority of patients treated with a single FLT3 inhibitor experienced only transient and partial response because of the development of drug resistance, which hinders treatment with FLT3-TKIs. The development of drug resistance during the treatment of hematologic malignance has been a challenging issue for TKIs. 5-7 Activated FLT3-kinase mutations eventually induce transformation and tumorigenesis in hematopoietic cells and suppress normal myeloid differentiation and therefore are attractive therapeutic targets to treat AML.
#Weisberg calcusyn Activator#
4 FLT3-ITD or FLT3-TKD mutants undergo constitutive autophosphorylation of FLT3, causing aberrant signaling activation of several pathways such as Ras/mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription (STAT) 5, and protein kinase B (AKT). 2, 3 FLT3 point mutations within the activation loop of the tyrosine kinase domain (FLT3-TKD) have also been detected in ∼7% of AML patients. 1 In 20% to 25% of AML patients, the FLT3 gene acquires an internal tandem duplication in the juxtamembrane domain of FLT3 (FLT3-ITD), and this is associated with poor prognosis. Fms-like tyrosine receptor kinase (FLT) 3 plays an important role in normal hematopoiesis and leukemogenesis and is expressed in most AML blasts. Thus, G-749 appears to be a promising next-generation drug candidate for the treatment of relapsed and refractory AML patients with various FLT3-ITD/FLT3-TKD mutants and further shows the ability to overcome drug resistance.Īcute myeloid leukemia (AML) is an aggressive hematologic disorder in which the hematopoietic progenitor cells lose their ability to differentiate normally and continue to proliferate.
Oral administration of G-749 yielded complete tumor regression and increased life span in animal models. Furthermore, it displayed potent antileukemic activity in bone marrow blasts from AML patients regardless of FLT3 mutation status, including those with little or only minor responses to AC220 or PKC412. G-749 retained its inhibitory potency in various drug-resistance milieus such as patient plasma, FLT3 ligand surge, and stromal protection. G-749 is a novel FLT3 inhibitor that showed potent and sustained inhibition of the FLT3 wild type and mutants including FLT3-ITD, FLT3-D835Y, FLT3-ITD/N676D, and FLT3-ITD/F691L in cellular assays. Aberrant activations of Fms-like tyrosine receptor kinase (FLT) 3 are implicated in the pathogenesis of 20% to 30% of patients with acute myeloid leukemia (AML).