scholarly journals Optimization of Imidazo[4,5-b]pyridine-Based Kinase Inhibitors: Identification of a Dual FLT3/Aurora Kinase Inhibitor as an Orally Bioavailable Preclinical Development Candidate for the Treatment of Acute Myeloid Leukemia

2012 ◽  
Vol 55 (20) ◽  
pp. 8721-8734 ◽  
Author(s):  
Vassilios Bavetsias ◽  
Simon Crumpler ◽  
Chongbo Sun ◽  
Sian Avery ◽  
Butrus Atrash ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Preclinical Development ◽  
Orally Bioavailable ◽  
Acute Myeloid

scholarly journals A phase 1 study of AMG 900, an orally administered pan-aurora kinase inhibitor, in adult patients with acute myeloid leukemia

2017 ◽  
Vol 92 (7) ◽  
pp. 660-667 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Michael W. Schuster ◽  
Nitin Jain ◽  
Anjali Advani ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Aurora Kinase ◽  
Adult Patients ◽  
Aurora Kinase Inhibitor ◽  
Phase 1 Study ◽  
Acute Myeloid

Response rates in patients with relapsed/refractory acute myeloid leukemia with FLT3-ITD mutation using 5-azacitadine plus sorafenib.

2012 ◽  
Vol 30 (30_suppl) ◽  
pp. 24-24 ◽  
Author(s):  
Mona Lisa Alattar ◽  
Hagop Kantarjian ◽  
Mark J. Levis ◽  
Mary Ann Richie ◽  
Naval Guastad Daver ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Intensive Therapy ◽  
Response Assessment ◽  
Flt3 Ligand ◽  
Refractory Acute Myeloid Leukemia ◽  
Putative Mechanism ◽  
Acute Myeloid

24 Background: Outcome of patients with relapsed acute myeloid leukemia (AML) with FLT3-ITD mutation is poor. Elevated FLT3 ligand levels (FL) secondary to cytotoxic chemotherapy is a putative mechanism of resistance to the FLT3 kinase inhibitors. We hypothesized that FL levels will be lower when combining sorafenib with less intensive therapy such as 5-Azacytidine (5-Aza). This study was conducted to evaluate the efficacy and tolerability of the combination of sorafenib and 5-Aza in patients with refractory or relapsed AML with FLT3-ITD mutation. Methods: Patients were eligible if they had relapsed or refractory AML and were 18 years of age or older. They received 5-Aza 75 mg/m2 IV daily x 7 days and sorafenib 400 mg PO BID continuously; cycles were repeated in approximately one month intervals. Results: 38 patients with AML with a median age of 60 years (range, 24-87) were enrolled. 4 were inevaluable as they never received therapy or discontinued it before response assessment. FLT-3-ITD was detected in 30 (88%) patients. They had received a median of 2 prior treatments (range, 0-6); 13 (38%) had received ≥ 3 prior regimens and 8 had failed prior FLT3 kinase inhibitor. Response rate was 41%, including 6 (17%) with CRi, 4 (12) with CRp, 3 (9%) with CR, and 1(3%) PR. The median time to achieving CR/CRi was 2 cycles (Range, 1-6) and the median duration of CR/CRi was 3 months (Range, 1–12). Conclusions: Combination of 5-Aza and sorafenib is effective for patients with relapsed AML with FLT-3-ITD mutation.

scholarly journals Identification of a Pharmacodynamic Biomarker for SEL24/MEN1703, a First-in-Class Dual PIM/FLT3 Kinase Inhibitor for Acute Myeloid Leukemia, and Its Implementation in the First-in-Human Study CLI24-001

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5087-5087
Author(s):  
Andrea Tomirotti ◽  
Giuseppe Merlino ◽  
Alessio Fiascarelli ◽  
Simone Baldini ◽  
Alessia Tagliavini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Human Study ◽  
Pim Kinases ◽  
Equity Ownership ◽  
Acute Myeloid

SEL24/MEN1703 is a first-in-class, orally available, dual PIM/FLT3 kinase inhibitor currently investigated in patients with Acute Myeloid Leukemia (AML) in the first-in-human study CLI24-001 (NCT03008187). PIM and FLT3 kinases are considered to play an important role in AML and are inhibited by SEL24/MEN1703. Moreover, there is evidence that inhibition of PIM kinases might contribute to overcoming acquired resistance induced by approved FLT3 inhibitors1. In AML, different signal transducers in the FLT3 pathway are substrates of kinases. Therefore, their phosphorylation levels might be modulated by kinase inhibitors and may be exploited as a potential pharmacodynamic biomarker in clinical development. In particular, phosphorylation of S6, 4E-BP1, and STAT5 is regulated by both FLT3 and PIM1/2. Thus, the objective of this investigation was to identify the most promising pharmacodynamic biomarker/s for implementation in the clinical trials of SEL24/MEN1703. Initially, we assessed the in vitro cytotoxic effect of SEL24/MEN1703 in a panel of 26 AML cell lines harboring different genetic mutations, to identify suitable cell lines for subsequent experiments. In the selected panel of AML cell lines, SEL24/MEN1703 resulted in the inhibition of phosphorylation of S6, 4-EBP1 and STAT5 as measured by immunoblotting. Notably, the reduction in phosphorylated S6 (pS6) in response to SEL24/MEN1703 was particularly evident. Since SEL24/MEN1703 displays a broad cytotoxic activity in AML cell lines, we clustered sensitive and resistant cell lines considering 0.5 μM as the IC50 cut-off value. Then, we investigated the relationship between SEL24/MEN1703 cytotoxic activity in AML cell lines and the inhibition of the above mentioned phosphorylated proteins in a 24-hour cytotoxic assay, showing a correlation between IC50 and the reduction of pS6 (Pearson correlation coefficient: -0.6905, R2= 0.477). To further confirm the in vitro data, SEL24/MEN1703 ability to modulate phosphoproteins was assessed also in xenograft mice bearing MOLM-16 cell line. The phosphorylation status of S6, 4E-BP1 and STAT5 was analyzed by immunoblot in tumor tissues from mice treated at 25 mg/kg of SEL24/MEN1703 at baseline and at 4, 8, and 16 hours after treatment. Results showed that also in vivo, SEL24/MEN1703 administration resulted in a decrease of pS6, with maximum reduction in this parameter observed 4 hours after the administration of the investigational compound. Based on these results, pS6 was identified as the pharmacodynamic biomarker to be implemented in the CLI24-001 clinical trial. Among different available methods, flow cytometry was selected as the preferred platform to analyze patient samples, because of its ability to provide quantitative assessment of cellular events and pharmacodynamic evaluation in a selected, relevant cell subpopulation, such as the AML blast cells. The assessment of pS6 in the clinical trial is planned both at baseline and at cycle 1 day 14 for whole blood and bone marrow. In addition, pS6 levels will be measured in whole blood at additional time points during treatment cycles. We have implemented the measurement of pS6 in the CLI24-001 trial, and pS6 levels as well as their relationship with the main pharmacokinetic parameters in patients treated with SEL24/MEN703 at 100 and 125 mg will be presented. 1Green A.S. et al., Pim kinases modulate resistance to FLT3 tyrosine kinase inhibitors in FLT3-ITD acute myeloid leukemia, Sci Adv, 2015 Disclosures Tomirotti: Menarini Ricerche S.p.A.: Employment. Merlino:Menarini Ricerche S.p.A.: Employment. Fiascarelli:Menarini Ricerche S.p.A.: Employment. Baldini:Menarini Ricerche S.p.A.: Employment. Tagliavini:Menarini Ricerche S.p.A: Employment. Borella:Menarini Ricerche S.p.A.: Employment. Mazan:Selvita S.A.: Employment. Brzózka:Selvita S.A.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Bressan:Menarini Ricerche S.p.A.: Employment. Pellacani:Menarini Ricerche S.p.A.: Employment; Amgen: Equity Ownership. Salerno:Menarini Ricerche S.p.A.: Employment. Binaschi:Menarini Ricerche S.p.A.: Employment. Bellarosa:Menarini Ricerche S.p.A.: Employment.

The Role of Kinase Inhibitors in the Treatment of Patients with Acute Myeloid Leukemia

2013 ◽  
pp. 313-318
Author(s):  
Catherine C. Smith ◽  
Neil P. Shah
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Clinical Success ◽  
Cyclin Dependent Kinases ◽  
Downstream Signaling ◽  
Flt3 Inhibitors ◽  
Acute Myeloid

Multiple small molecule kinase inhibitors are currently undergoing development for the treatment of acute myeloid leukemia (AML). Recently, selective and potent FLT3 inhibitors such as AC220 (quizartinib) have proven clinically effective in patients with AML with FLT3 internal tandem duplication (ITD) mutations, but inhibitors of other pathologically activated kinases in AML such as c-KIT and JAK2 have achieved less clinical success. Other classes of inhibitors currently undergoing clinical development target mediators of downstream signaling pathways such as mTOR and MEK or cell cycle machinery such as aurora kinases, PLK1, or cyclin-dependent kinases. Other than FLT3 inhibitors, most inhibitors have achieved only rare bone marrow responses, and kinase inhibitor therapy in AML remains investigational. Continuing efforts to develop kinase inhibitors for the treatment of AML will require careful selection of patients for clinical trials, translational studies to characterize responders, and investigation of combination therapy that may be capable of improving response rates and duration.

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