Acute myeloid leukemia (AML) is an aggressive cancer, representing 90% of all adult acute leukemias, with an estimated incidence of 200,000 cases each year worldwide. Noticeably malignant cells, in the majority of AML patients, possess aberrantly expressed FLT3. The corresponding tumor-cell genotyping indicates that 25–30% of the AML blasts carry FLT3 mutations. The molecular characterization of these FLT3 mutations has revealed that they contain either internal tandem duplications (FLT3-ITD) in the juxtamembrane region (17–34%) or point mutations at the kinase domain (7%). Therefore, FLT3 has emerged as a promising target in therapy of AML. The first and second generation of the FLT3 inhibitors such as CEP-701, MLN-518, PKC-412, Sunitinib, Sorafenib, and AC220 are under clinical trial for AML treatment. However, their clinical responses have been below expectation likely due to the influence of plasma inhibitory activity, lack of strong inhibition of downstream effectors involved in aberrant activation of growth pathway, and lack of substantial and sustained inhibition of FLT3 activity, consequently resulting in drug resistance.
To address and overcome the key issues leading to several known drug resistances, we have developed a series of novel and highly selective FLT3 inhibitors possessing extreme potency against clinically known FLT3-mutants. One of our leads, SKI-G-801 (G-801), showed IC50 of 0.3 nM for FLT3 and IC50 of 2.1 nM in MV4–11 cells. Furthermore, it also showed IC50 of 3.1 nM in model cell line BaF3 expressing FLT3 D835Y whereas AC220 and PKC412 showed IC50s of 52.4 nM and 11.4 nM in the BaF3 cells, respectively. The tight binding property and the high potency of our lead candidates led to a strong inhibitory activity in the cell model in the presence of human plasma; FLT3 phosphorylation was inhibited by G-801 with IC50 of 9.9nM, while by PKC412 with IC50 of >1000 nM in the human plasma. In addition, a significant tumor regression of 85–100% was observed in a mouse xenograft model using MV4–11 cells by G-801 via oral administration for 28 days. Moreover, a synergistic effect of our lead compounds with AraC was more significant in RS4–11 cells than the known FLT3 inhibitors with AraC. These desirable characteristics of our lead candidates would ostensibly overcome the documented drug resistance confronted by previous FLT3 targeted inhibitors such as AC220, PKC-412, and CEP701. One of our lead candidates is expected to enter preclinical study soon.
Therefore, we are confident that our lead candidate will be a promising acute myeloid leukemia drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C196.
