title: AMG 925 is a dual FLT3/CDK4 inhibitor with the potential to overcome FLT3 inhibitor resistance in acute myeloid leukemia.
abstract: 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 μmol/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.
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California. congl@amgen.com.
authors.forename: Cong
authors.initials: C
authors.lastname: Li
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Liqin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Lingming
authors.initials: L
authors.lastname: Liang
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xia
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Xianghong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Katie
authors.initials: K
authors.lastname: Newhall
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Angus
authors.initials: A
authors.lastname: Sinclair
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kamb
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Dineli
authors.initials: D
authors.lastname: Wickramasinghe
authors.affiliation: Amgen Discovery Research, Amgen Inc., South San Francisco, California.
authors.forename: Kang
authors.initials: K
authors.lastname: Dai
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D052160:Benzothiazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D002999:Clone Cells; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009287:Naphthyridines / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C000589290:2-hydroxy-1-(2-((9-(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; D052160:Benzothiazoles; D006575:Heterocyclic Compounds, 3-Ring; D009287:Naphthyridines; D010671:Phenylurea Compounds; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C544967:quizartinib; D051941:fms-Like Tyrosine Kinase 3; D051358:Cyclin-Dependent Kinase 4; C500026:palbociclib