Purity: > 98%
AAE871(cas 289479-07-8) is a type I FLT3 inhibitor.
1. Genes Cancer. 2010 Oct;1(10):1021-32. doi: 10.1177/1947601910396505.
Antileukemic Effects of Novel First- and Second-Generation FLT3 Inhibitors:
Weisberg E(1), Roesel J, Furet P, Bold G, Imbach P, Flörsheimer A, Caravatti G,
Jiang J, Manley P, Ray A, Griffin JD.
(1)Department of Medical Oncology/Hematologic Neoplasia, Dana Farber Cancer
Institute, Boston, MA, USA.
Constitutively activated mutant FLT3 has emerged as a promising target for
therapy for the subpopulation of acute myeloid leukemia (AML) patients who harbor
it. The small molecule inhibitor, PKC412, targets mutant FLT3 and is currently in
late-stage clinical trials. However, the identification of PKC412-resistant
leukemic blast cells in the bone marrow of AML patients has propelled the
development of novel and structurally distinct FLT3 inhibitors that have the
potential to override drug resistance and more efficiently prevent disease
progression or recurrence. Here, we present the novel first-generation /type II/
FLT3 inhibitors, AFG206, AFG210, and AHL196, and the second-generation /type II/
derivatives and AST487 analogs, AUZ454 and ATH686. All agents potently and
selectively target mutant FLT3 protein kinase activity and inhibit the
proliferation of cells harboring FLT3 mutants via induction of apoptosis and cell
cycle inhibition. Cross-resistance between /type I/ inhibitors, PKC412 and
AAE871, was demonstrated. While cross-resistance was also observed between /type
I/ and first-generation /type II/ FLT3 inhibitors, the high potency of the
second-generation /type II/ inhibitors was sufficient to potently kill /type I/
inhibitor-resistant mutant FLT3-expressing cells. The increased potency observed
for the second-generation /type II/ inhibitors was observed to be due to an
improved interaction with the ATP pocket of FLT3, specifically associated with
introduction of a piperazine moiety and placement of an amino group in position 2
of the pyrimidine ring. Thus, we present 2 structurally novel classes of FLT3
inhibitors characterized by high selectivity and potency toward mutant FLT3 as a
molecular target. In addition, presentation of the antileukemic effects of /type
II/ inhibitors, such as AUZ454 and ATH686, highlights a new class of highly
potent FLT3 inhibitors able to override drug resistance that less potent /type I/
inhibitors and /type II/ first-generation FLT3 inhibitors cannot.