High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells

Zeng, Zhihong; Ly, Charlie; Daver, Naval; Cortes, Jorge; Kantarjian, Hagop M.; Andreeff, Michael; Konopleva, Marina

doi:10.1007/s00277-021-04493-0

Cited by 5 publications

(2 citation statements)

References 45 publications

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“…Based on the training set (Figure S1), which consists of approved CDK4/6 inhibitors such as palbociclib, ribociclib, and abemaciclib and clinical candidates such as G1T38 and AMG925, − pharmacophore models 1–10 were generated (Table and Figure S2), which further mapped with positive ( A1 - A6 , Figure S3) and negative ( N1 – N9 , Figure S4) molecules in the decoy set to evaluate sensitivity and specificity. The validation results were described as a heatmap (Figure A) and receiver operating characteristic (ROC) curve (Figure S5), and pharmacophore model 7 (Figure B) was found to exhibit the best quality in identifying positive molecules and eliminating negative molecules.…”

Section: Resultsmentioning

confidence: 99%

Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

Chen

Cheng

et al. 2022

J. Med. Chem.

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Breast cancer is the most common tumor in women, and selective cyclin-dependent kinase (CDK) 4/6 inhibitors played an important role in the treatment of breast cancer. Therefore, discovering selective CDK4/6 inhibitors with great safety and potent efficacy is beneficial for the breast cancer treatment. In our work, the lead compound 8 was identified through virtual screening; then, systematic structural optimization was conducted to afford 42, which exhibited strong inhibition on CDK4/6 and showed high selectivity among 205 kinases. 42 possessed excellent safety profiles (LD 50 > 5,000 mg/kg), favorable pharmacokinetic properties (F % = 43%), and potent efficacy in reducing the burden of breast cancer in vivo. In conclusion, we offered a highly selective CDK4/6 inhibitor, which could be used as a great candidate for further preclinical studies of breast cancer.

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Section: Resultsmentioning

confidence: 99%

Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

Chen

Cheng

et al. 2022

J. Med. Chem.

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“… 178 AMG925, a novel dual inhibitor of FLT3/CDK4-6 induced apoptosis in both WT and mutant FLT3 AML cell lines and primary blasts. 179 KX2-391 is a recently identified dual FLT3/Tubulin inhibitor with promising resistance-reversion activity against FLT3-ITD and FLT3-ITD-D835/F691 mutation in in vitro cell lines, a murine model, and patient blasts. 180 Inhibition of JAK2 and FLT3 at the same time could be a possible strategy to eradicate resistant cells with FLT3 mutations.…”

Section: Designing Novel Flt3imentioning

confidence: 99%

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Tecik¹,

Adan²

2022

OTT

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FMS-like tyrosine kinase 3 (FLT3) is mutated in approximately 30% of acute myeloid leukemia (AML) patients. The presence of FLT3-ITD (internal tandem duplication, 20–25%) mutation and, to a lesser extent, FLT3-TKD (tyrosine kinase domain, 5–10%) mutation is associated with poorer diagnosis and therapy response since the leukemic cells become hyperproliferative and resistant to apoptosis after continuous activation of FLT3 signaling. Targeting FLT3 has been the focus of many pre-clinical and clinical studies. Hence, many small-molecule FLT3 inhibitors (FLT3is) have been developed, some of which are approved such as midostaurin and gilteritinib to be used in different clinical settings, either in combination with chemotherapy or alone. However, many questions regarding the best treatment strategy remain to be answered. On the other hand, various FLT3-dependent and -independent resistance mechanisms could be evolved during FLT3i therapy which limit their clinical impact. Therefore, identifying molecular mechanisms of resistance and developing novel strategies to overcome this obstacle is a current interest in the field. In this review, recent studies of approved FLT3i and knowledge about major resistance mechanisms of clinically approved FLT3i’s will be discussed together with novel treatment approaches such as designing novel FLT3i and dual FLT3i and combination strategies including approved FLT3i plus small-molecule agents targeting altered molecules in the resistant cells to abrogate resistance. Moreover, how to choose an appropriate FLT3i for the patients will be summarized based on what is currently known from available clinical data. In addition, strategies beyond FLT3i’s including immunotherapeutics, small-molecule FLT3 degraders, and flavonoids will be summarized to highlight potential alternatives in FLT3-mutated AML therapy.

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Leukemic stem cell signatures in Acute myeloid leukemia- targeting the Guardians with novel approaches

Thakral

Gupta

Khan

2022

Stem Cell Rev and Rep

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High-throughput proteomic profiling reveals mechanisms of action of AMG925, a dual FLT3-CDK4/6 kinase inhibitor targeting AML and AML stem/progenitor cells

Cited by 5 publications

References 45 publications

Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

Discovery, Optimization, and Evaluation of Selective CDK4/6 Inhibitors for the Treatment of Breast Cancer

Therapeutic Targeting of FLT3 in Acute Myeloid Leukemia: Current Status and Novel Approaches

Leukemic stem cell signatures in Acute myeloid leukemia- targeting the Guardians with novel approaches

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