1401033-86-0

Basic information

• Product Name: AMG 925
• Synonyms: AMG 925;1-[7,8-Dihydro-2-[[9-(trans-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl]amino]-1,6-naphthyridin-6(5H)-yl]-2-hydroxyethanone;2-Hydroxy-1-(2-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-;Ethanone, 1-[7,8-dihydro-2-[[9-(trans-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl]amino]-1,6-naphthyridin-6(5H)-yl]-2-hydroxy-
• CAS NO: 1401033-86-0
• Molecular Formula: C₂₆H₂₉N₇O₂
• Molecular Weight: 471.57
• Mol File: 1401033-86-0.mol

Chemical Properties

• Boiling Point: 712.3±70.0 °C(Predicted)
• Appearance: /
• Density: 1.48±0.1 g/cm3(Predicted)
• Solubility: insoluble in DMSO; insoluble in H2O; insoluble in EtOH
• PKA: 13.41±0.10(Predicted)
• CAS DataBase Reference: AMG 925(CAS DataBase Reference)
• NIST Chemistry Reference: AMG 925(1401033-86-0)
• EPA Substance Registry System: AMG 925(1401033-86-0)

Safety Data

• Hazardous Substances Data: 1401033-86-0(Hazardous Substances Data)

Usage

Uses

Used in Oncology:
AMG 925 is used as a FLT3 and CDK4 dual kinase inhibitor for the treatment of various cancers, particularly those with FLT3 mutations or overactivation. Its application is based on its ability to selectively target and inhibit the activity of FLT3 and Cdk4, which are key drivers of cancer cell proliferation and survival.
Used in AML Treatment:
AMG 925 is used as a targeted therapy for acute myeloid leukemia (AML) due to its effectiveness in reducing intratumor levels of pSTAT5 and pRb, which are involved in the signaling pathways that promote the growth and survival of AML cells. This leads to the inhibition of tumor growth in AML patients.
Used in Cancer Research:
AMG 925 is used as a research tool for studying the role of FLT3 and Cdk4 in cancer cell proliferation and survival. Its ability to selectively inhibit these targets makes it a valuable compound for investigating the underlying mechanisms of cancer development and progression, as well as for identifying potential therapeutic strategies for cancer treatment.

references

[1] keegan k, li c, li z, ma j, ragains m, coberly s, hollenback d, eksterowicz j, liang l, weidner m, huard j, wang x, alba g, orf j, lo mc, zhao s, ngo r, chen a, liu l, carlson t, quéva c, mcgee lr, medina j, kamb a, wickramasinghe d, dai k. preclinical evaluation of amg 925, a flt3/cdk4 dual kinase inhibitor for treating acute myeloid leukemia. mol cancer ther. 2014 apr;13(4):880-9.

Upstream product

• 1588959-12-9 C₁₁H₁₅BrClN₃ 
• 1588959-18-5 C₁₁H₁₇BrN₄ 
• 1588959-28-7 C₁₆H₂₀ClN₅ 
• 79-14-1 glycolic Acid 
• 1401033-82-6 9-((1r,4r)-4-methylcyclohexyl)-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine 
• 2523-55-9 trans-4-methylcyclohexanamine 
• 1401034-47-6 2-(2-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-oxoethyl acetate 
• 1401034-46-5 tert-butyl 2-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 
• 1401034-45-4 9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine 
• 1401034-44-3 5-(3-fluoropyridin-4-yl)-N⁴-((1R,4R)-4-methylcyclohexyl)pyrimidine-2,4-diamine 
• 1401034-43-2 5-iodo-N⁴-((1R,4R)-4-methylcyclohexyl)pyrimidine-2,4-diamine 
• 1401034-42-1 N⁴-((1r,4r)-4-methylcyclohexyl)pyridine-2,4-diamine 
• 33483-65-7 trans-4-methylcyclohexylamine hydrochloride 
• 766545-20-4 2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine hydrochloride 

Downstream Products

• 1401034-19-2 2-hydroxy-1-(2-((9-((1R,4R)-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethanone hydrochloride 

Relevant articles and documents

Multi-kilo delivery of AMG 925 featuring a buchwald-hartwig amination and processing with insoluble synthetic intermediates

The development of a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale is reported herein. The hydrochloride salt of AMG 925 was prepared in 23% overall yield over eight steps from commercially available raw materials, and more than 8 kg of the target molecule were delivered. The synthetic route features a Buchwald-Hartwig amination using BrettPhos as ligand and conducted to afford 12 kg of product in a single batch. In addition, this work highlights the challenges associated with the use of poorly soluble process intermediates in the manufacture of active pharmaceutical ingredients. Creative solutions had to be devised to conduct seemingly routine activities such as salt removal, pH adjustment, and heavy metal scavenging due to the low solubility of the process intermediates. Finally, a slurry-to-slurry amidation protocol was optimized to allow for successful scale-up.

Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3

We describe the structural optimization of a lead compound 1 that exhibits dual inhibitory activities against FLT3 and CDK4. A series of pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidine derivatives was synthesized, and SAR analysis, using cell-based assays, led to the discovery of 28 (AMG 925), a potent and orally bioavailable dual inhibitor of CDK4 and FLT3, including many FLT3 mutants reported to date. Compound 28 inhibits the proliferation of a panel of human tumor cell lines including Colo205 (Rb +) and U937 (FLT3WT) and induced cell death in MOLM13 (FLT3ITD) and even in MOLM13 (FLT3ITD, D835Y), which exhibits resistance to a number of FLT3 inhibitors currently under clinical development. At well-tolerated doses, compound 28 leads to significant growth inhibition of MOLM13 xenografts in nude mice, and the activity correlates with inhibition of STAT5 and Rb phosphorylation.

FUSED TRICYCLIC DUAL INHIBITORS OF CDK 4/6 AND FLT3

Compounds of Formula I are useful inhibitors of CDK 4, CDK6, and FLT3. Such compounds are useful in treating cancer and various other disease conditions. Compounds of Formula I have the following structure: where R1 is a group of Formula IA, Formula IB, Formula IC, or Formula ID and the definitions of the other variables are provided herein.