Arylcarboxyamino-substituted diaryl ureas as potent and selective FLT3 inhibitors

Patel, Hitesh; Grotzfeld, Robert M.; Lai, Andiliy; Mehta, Siddharth; Milanov, Zdravko V.; Qi, Chaorong; Sprankle, Kelly G.; Carter, Todd A.; Velasco, Anne Marie; Fabian, Miles A.; James, Joyce; Treiber, Daniel K.; Lockhart, David J.; Zarrinkar, Patrick P.; Bhagwat, Shripad S.

doi:10.1016/j.bmcl.2009.07.024

Cited by 29 publications

(20 citation statements)

References 6 publications

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“…Diaryl ureas were identified as scaffolds that elicited potent inhibition of FLT3 [ 16 ]. The co-complex of quizartinib with FLT3 reveals important interactions that this moiety makes in the kinase active site.…”

Section: Resultsmentioning

confidence: 99%

“…In a recent review, we described the interactions that these clinically approved inhibitors exploit in the kinase active site [ 15 ]. In particular, FLT3 is potently inhibited by small molecules composed of a diaryl urea core scaffold, which were found to be efficacious in mouse models of the disease [ 16 ]. Chemical optimization of these compounds led to the discovery of quizartinib or AC220, which exhibits both selectivity for and potency against FLT3 [ 17 , 18 ].…”

Section: Introductionmentioning

confidence: 99%

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Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)

et al. 2015

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More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an “Abl-like” inactive conformation with the activation loop stabilized in the “DFG-out” orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)

et al. 2015

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“…Various reports described the antitumor activity of kinase inhibitors containing a diaryl urea functional group. 35,36 Sorafenib, a diaryl urea multi-targeted inhibitor of several kinases, is a well-known example of a drug used for the treatment of advanced renal cell carcinoma (RCC) and unresectable hepatocellular carcinoma (HCC). 37 The diaryl urea portion of kinase inhibitors is highly conserved and shared by most type II kinase inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based novel dual kinase inhibitors of CK2 and GSK3β

et al. 2018

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“…This group was able to synthesize a series of very active FLT3 inhibitor agents that featured excellent oral bioavailability. The first compound in the series, "Compound 1" (AB-530) was found to be effective, as it induced tumor regression in a mouse xenograft model with human leukemia cell line MV4-11 cells (Patel et al 2009). However, the oral PK qualities of this drug at the higher doses tested did not lend itself to proceed with clinical development as this formulation demonstrated suboptimal solubility, deemed inadequate for a clinical agent.…”

Section: Drug Development Of Ac220 As Flt3 Inhibitormentioning

confidence: 98%

FLT3-ITD. Clinical (Sorafenib/AC220)

Cortes

Pemmaraju

2014

Targeted Therapy of Acute Myeloid Leukemia

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A plethora of new molecular abnormalities has been identified to be associated with acute myelogenous leukemia (AML). These markers have contributed to a more accurate prognostic stratification of these patients, and have nurtured hopes for effective targeted therapies. One such abnormality is the FMS-like tyrosine kinase 3, or FLT3 gene mutation, present in approximately 30 % of AML patients. The presence of the FLT3 internal tandem duplication (FLT3-ITD) confers a poorer prognosis with higher risk of relapse for this subset of AML patients. Rapid development of a large number of FLT3 tyrosine kinase inhibitors (TKIs) has enabled an exciting era of research and treatment for patients with these abnormalities. The expectation is that FLT3 inhibition may offer improvements in outcomes in this poor prognosis group of patients. Early data suggest that this promise may be materializing for patients. This chapter will focus on two of these FLT3 inhibitors, sorafenib (Nexavar®) and AC220 (quizartinib).

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Arylcarboxyamino-substituted diaryl ureas as potent and selective FLT3 inhibitors

Cited by 29 publications

References 6 publications

Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)

Crystal Structure of the FLT3 Kinase Domain Bound to the Inhibitor Quizartinib (AC220)

Design, synthesis, and evaluation of 4,5,6,7-tetrahydrobenzo[d]thiazole-based novel dual kinase inhibitors of CK2 and GSK3β

FLT3-ITD. Clinical (Sorafenib/AC220)

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