Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

Li, Zhihong; Wang, Xianghong; Eksterowicz, John; Gribble, Michael; Alba, Grace; Ayres, Merrill; Carlson, Timothy J.; Chen, Ada; Chen, Xiaoqi; Robert, Caroline; Connors, Richard; DeGraffenreid, Michael; Deignan, Jeffrey; Duquette, Jason; Fan, Pingchen; Fisher, Benjamin; Fu, Jiasheng; Huard, Justin; Kaizerman, Jacob A.; Keegan, Kathleen; Liu, Cong; Li, Kexue; Li, Yunxiao; Liang, Lingming; Li, Wen; Lively, Sarah; Lo, Mei-Chu; Ma, Ji; McMinn, Dustin L.; Mihalic, Jeffrey T.; Modi, Kriti; Ngo, Rachel; Pattabiraman, Kanaka; Piper, Derek E.; Quéva, Christophe; Ragains, Mark L.; Suchomel, Julia; Thibault, Steve; Walker, Nigel; Wang, Xiaodong; Wang, Zhong Lin; Wanska, Malgorzata; Wehn, Paul M.; Weidner, Margaret F.; Zhang, Alex J.; Zhao, Xiaoning; Kamb, Alexander; Wickramasinghe, Dineli; Dai, Kang; McGee, Lawrence R.; Medina, Julio C.

doi:10.1021/jm500118j

Cited by 61 publications

(57 citation statements)

References 24 publications

(48 reference statements)

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“…As previously reported (18,19), AMG 925 is a potent and selective dual FLT3/CDK4 inhibitor. It potently inhibits FLT3 and CDK4 kinases and the growth of FLT3-dependent AML cell lines bearing FLT3-ITD, MOLM13, and MV4-11 (Supplementary Table S1 Table S1).…”

Section: Isolation and Characterization Of Amg 925-resistant Aml Cellsupporting

confidence: 63%

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AMG 925 Is a Dual FLT3/CDK4 Inhibitor with the Potential to Overcome FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

Liu

Liang

et al. 2015

Molecular Cancer Therapeutics

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Resistance to FLT3 inhibitors is a serious clinical issue in treating acute myelogenous leukemia (AML). AMG 925, a dual FLT3/CDK4 inhibitor, has been developed to overcome this resistance. It is hypothesized that the combined inhibition of FLT3 and CDK4 may reduce occurrence of the FLT3 resistance mutations, and thereby prolong clinical responses. To test this hypothesis, we attempted to isolate AML cell clones resistant to AMG 925 or to FLT3 inhibitors. After a selection of over 8 months with AMG 925, we could only isolate partially resistant clones. No new mutations in FLT3 were found, but a 2-to 3-fold increase in total FLT3 protein was detected and believed to contribute to the partial resistance. In contrast, selection with the FLT3 inhibitors sorafenib or AC220 (Quizartinib), led to a resistance and the appearance of a number of mutations in FLT3 kinase domains, including the known hot spot sites D835 and F691. However, when AC220 was combined with the CDK4 inhibitor PD0332991 (palbociclib) at 0.1 mmol/L or higher, no resistance mutations were obtained, indicating that the CDK4-inhibiting activity of AMG 925 contributed to the failure to develop drug resistance. AMG 925 was shown to potently inhibit the FLT3 inhibitor-resistant mutation D835Y/ V. This feature of AMG 925 was also considered to contribute to the lack of resistance mutations to the compound. Together, our data suggest that AMG 925 has the potential to reduce resistance mutations in FLT3 and may prolong clinical responses.

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Section: Isolation and Characterization Of Amg 925-resistant Aml Cellsupporting

confidence: 63%

“…AMG 925 is a novel potent and selective FLT3/CDK4 dualkinase inhibitor designed to address the issue of resistance to FLT3 inhibitors (18,19). CDK4 is a Cyclin D-dependent kinase that plays an essential role in integrating external growth signals and promoting progression from G 1 to S phase of the mammalian cell cycle (20,21).…”

Section: Introductionmentioning

confidence: 99%

AMG 925 Is a Dual FLT3/CDK4 Inhibitor with the Potential to Overcome FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

Liu

Liang

et al. 2015

Molecular Cancer Therapeutics

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“…Moreover, phosphorylation of Thr172 in the T-loop does not result in the activation of the enzyme bound to cyclin D1. Furthermore, there are several 3.10 1JOW CDK6 -Vcyclin -9-cyclopentyl-N-(5-piperazin-1-ylpyridin-2-yl)pyrido [4,5]pyrrolo[1,2-d]pyrimidin-2-amine 109 2.90 4TTH CDK6 -Vcyclin -Aminopurvalanol 114 2.80 2F2C CDK6 -Vcyclin -Fisetin 117 2.90 1XO2 CDK6 -Vcyclin -PD0332991 114 3.00 2EUF CDK6 -Kcyclin -p18 INK4c 118 2 111 2.70 4EZ5 CDK6 -1H-benzimidazol-2-yl(1H-pyrrol-2-yl)methanone 111 2.31 4AUA CDK6 -4-[3-(1-methylethyl)-1H-pyrazol-4-yl]-N-(1-methylpiperidin-4-yl)pyrimidin-2-amine 119 2.60 3NUP CDK6 -4-[5-chloro-3-(1-methylethyl)-1H-pyrazol-4-yl]-N-(5-piperazin-1-ylpyridin-2-yl)pyrimidin-2-amine 119 2.70 3NUX CDK6 -p16 INK4a 83 3.40 1BI7 CDK6 -p19 INK4d 74,83 1.90 1BLX 2.80 1BI8 lines of evidence showing that CDK4 might not even be phosphorylated by CAK. 77,78 The INK4 family of CDK inhibitors (CDKIs) which include p16 INK4a , p15 INK4b , p18 INK4c , and p19 INK4d are specific to CDK4 and CDK6.…”

Section: Structural Features and Regulationmentioning

confidence: 99%

“…92,107,108 In addition to the above clinical experimental drug compounds, a few pre-clinical CDK4/6 inhibitors, i.e., 7X, AMG925, Compound 6, Compound A and PD0183812, have been reported. [109][110][111][112][113] The chemical structures and CDK inhibitory activity of these compounds are summarized in Table 3. A close examination of the chemical structures of PD0332991, LEE011, LY2835219, AMG925 and Compound A reveals a general N-NH-N sequence of the pyrimidine-amine-pyridine or pyrazineamine-thiazole system.…”

Section: Compoundmentioning

confidence: 99%

“…For example, pyridine in AMG 925 has been shown to form an edge to face aromaticaromatic contact with the gatekeeper residue Phe98. 109,111 Docking and scoring of 7X (Table 3), which is highly structurally similar to PD0332991, have identified a binding orientation different from that of PD0332991. This has been attributed to the rigidity and higher electron withdrawing effect of the cyano group when compared with the acetyl group.…”

Section: Compoundmentioning

confidence: 99%

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Targeting CDK6 in cancer: State of the art and new insights

et al. 2015

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Cyclin-dependent kinase 6 (CDK6) plays a vital role in regulating the progression of the cell cycle. More recently, CDK6 has also been shown to have a transcriptional role in tumor angiogenesis. Up-regulated CDK6 activity is associated with the development of several types of cancers. While CDK6 is over-expressed in cancer cells, it has a low detectable level in non-cancerous cells and CDK6-null mice develop normally, suggesting a specific oncogenic role of CDK6, and that its inhibition may represent an ideal mechanism-based and low toxic therapeutic strategy in cancer treatment. Identification of selective small molecule inhibitors of CDK6 is thus needed for drug development. Herein, we review the latest understandings of the biological regulation and oncogenic roles of CDK6. The potential clinical relevance of CDK6 inhibition, the progress in the development of small-molecule CDK6 inhibitors and the rational design of potential selective CDK6 inhibitors are also discussed.

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Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

Bhurta

Bharate

2021

Medicinal Research Reviews

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Kinases have gained an important place in the list of vital therapeutic targets because of their overwhelming clinical success in the last two decades. Among various clinically validated kinases, the cyclin‐dependent kinases (CDK) are one of the extensively studied drug targets for clinical development. Food and Drug Administration has approved three CDK inhibitors for therapeutic use, and at least 27 inhibitors are under active clinical development. In the last decade, research and development in this area took a rapid pace, and thus the analysis of scaffold diversity is essential for future drug design. Available reviews lack the systematic study and discussion on the scaffold diversity of CDK inhibitors. Herein we have reviewed and critically analyzed the chemical diversity present in the preclinical and clinical pipeline of CDK inhibitors. Our analysis has shown that although several scaffolds represent CDK inhibitors, only the amino‐pyrimidine is a well‐represented scaffold. The three‐nitrogen framework of amino‐pyrimidine is a fundamental hinge‐binding unit. Further, we have discussed the selectivity aspects among CDKs, the clinical trial dose‐limiting toxicities, and highlighted the most advanced clinical candidates. We also discuss the changing paradigm towards selective inhibitors and an overview of ATP‐binding pockets of all druggable CDKs. We carefully analyzed the clinical pipeline to unravel the candidates that are currently under active clinical development. In addition to the plenty of dual CDK4/6 inhibitors, there are many selective CDK7, CDK9, and CDK8/19 inhibitors in the clinical pipeline.

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Discovery of AMG 925, a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3

Cited by 61 publications

References 24 publications

AMG 925 Is a Dual FLT3/CDK4 Inhibitor with the Potential to Overcome FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

AMG 925 Is a Dual FLT3/CDK4 Inhibitor with the Potential to Overcome FLT3 Inhibitor Resistance in Acute Myeloid Leukemia

Targeting CDK6 in cancer: State of the art and new insights

Analyzing the scaffold diversity of cyclin‐dependent kinase inhibitors and revisiting the clinical and preclinical pipeline

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