hh-gv678 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

Chronic myeloid leukemia (CML) is a malignant disease of the hematopoietic system with crucial pathogenic protein named BCR-ABL, which endangers the life of patients severely. As a milestone of targeted drug, Imatinib has achieved great success in the treatment of CML. Nevertheless, inevitable drug resistance of Imatinib has occurred frequently in clinical due to the several mutations in the BCR-ABL kinase. Subsequently, the second-generation of tyrosine kinase inhibitors (TKIs) against BCR-ABL was developed to address the mutants of Imatinib resistance, except T315I. To date, the third-generation of TKIs targeting T315I has been developed for improving the selectivity and safety. Notably, the first allosteric inhibitor has been in market which could overcome the mutations in ATP binding site effectively. Meanwhile, some advanced technology, such as proteolysis-targeting chimeras (PROTAC) based on different E3 ligand, are highly expected to overcome the drug resistance by selectively degrading the targeted proteins. In this review, we summarized the current research progress of inhibitors and degraders targeting BCR-ABL for the treatment of CML.

Topics: Antineoplastic Agents; Benzamides; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Protein Kinase Inhibitors; Pyrimidines

Flumatinib has been shown to be a more potent inhibitor of BCR-ABL1 tyrosine kinase than imatinib. We evaluated the efficacy and safety of flumatinib versus imatinib, for first-line treatment of chronic phase Philadelphia chromosome-positive chronic myeloid leukemia (CML-CP).. In this study, 394 patients were randomized 1:1 to flumatinib 600 mg once daily (. The rate of major molecular response (MMR) at 6 months (primary endpoint) was significantly higher with flumatinib than with imatinib (33.7% vs. 18.3%;. Patients receiving flumatinib achieved significantly higher rates of responses, and faster and deeper responses compared with those receiving imatinib, indicating that flumatinib can be an effective first-line treatment for CML-CP. This trial was registered at www.clinicaltrials.gov as NCT02204644.

Topics: Aminopyridines; Benzamides; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pharmaceutical Preparations; Piperazines; Pyrimidines; Treatment Outcome

The evolution of treatment options over the past 20 years has provided for a normal life expectancy for most patients with chronic myeloid leukemia. Currently approved tyrosine kinase inhibitors mainly differ in potency and side effect profile. Flumatinib goes for deep responses and good tolerability.

Topics: Aminopyridines; Benzamides; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Pharmaceutical Preparations; Protein Kinase Inhibitors

Flumatinib is an antineoplastic tyrosine kinase inhibitor used for the treatment of chronic myelogenous leukemia (CML). Its major metabolites in the circulation are N-desmethyl flumatinib (M1) and amide hydrolysis product (M3). To investigate the pharmacokinetics of flumatinib in CML patients, a simple, specific and rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of flumatinib and its two major metabolites in patient plasma. After a simple, one-step protein precipitation with methanol, flumatinib, its two metabolites, and internal standard (HHGV-E) were separated on a C(18) column using an isocratic mobile phase of methanol:5mM ammonium acetate:formic acid (60:40:0.4, v/v/v). A total chromatographic run time of 4.2 min was achieved. The detection was performed in multiple reaction monitoring mode, using the transitions of m/z 563→m/z 463 for flumatinib, m/z 549→m/z 463 for M1, m/z 303→m/z 175 for M3, and m/z 529→m/z 429 for HHGV-E. The method was linear over the concentration ranges of 0.400-400 ng/mL for flumatinib, 0.100-100 ng/mL for M1, and 0.200-200 ng/mL for M3, using only 50 μL of plasma. The intra- and inter-day precisions were less than 8.5% for flumatinib, 9.8% for M1, and 10.6% for M3 in terms of the relative standard deviation. The accuracy was within ± 2.2% for flumatinib, ± 6.0% for M1, and ± 9.9% for M3 in terms of relative error. The validated method was successfully applied to clinical pharmacokinetic studies of flumatinib mesylate in CML patients following oral administration at all dosage regimens.

Topics: Aminopyridines; Antineoplastic Agents; Benzamides; Chromatography, Liquid; Drug Stability; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Linear Models; Reproducibility of Results; Sensitivity and Specificity; Tandem Mass Spectrometry

Topics: Aminopyridines; Animals; Antineoplastic Agents; Apoptosis; Benzamides; Blotting, Western; Cell Proliferation; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Experimental; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Mice, Nude; Phosphorylation; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Pyridines; Pyrimidines; Receptor, Platelet-Derived Growth Factor beta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Survival Rate; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

4-(4-Methyl-piperazin-1-ylmethyl)-N-[6-methyl-5-(4-pyridin-3-yl-pyrimidin-2-ylamino)-pyridin-3-yl]-3-trifluoromethyl-benzamide (flumatinib, HH-GV678), an antineoplastic tyrosine kinase inhibitor, is currently in Phase I clinical trials in China for the treatment of chronic myelogenous leukemia (CML). The purpose of this study was to identify the metabolites of flumatinib in CML patients, with the aim of determining the main metabolic pathways of flumatinib in humans after oral administration. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry revealed 34 metabolites; 7 primary metabolites were confirmed by comparison with synthetic reference standards. The results show that the parent drug flumatinib was the main form recovered in human plasma, urine, and feces. The main metabolites of flumatinib in humans were the products of N-demethylation, N-oxidation, hydroxylation, and amide hydrolysis. In addition to these phase I metabolites, several phase II glucuronidation and acetylation products were detected in plasma, urine, and feces. The observed circulating metabolites included an N-demethylated metabolite (M1), two hydrolytic metabolites (M3, M4), oxidation metabolites (M2-1, M2-4, M2-7, M2-9, and M14), a glucuronide conjugate (M16-2), and several multiple metabolic products. Flumatinib was predominantly metabolized by amide bond cleavage to yield two corresponding hydrolytic products. By comparison with the related drug 4-(4-methyl-piperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-phenyl]-benzamide (imatinib), we concluded that the electron-withdrawing groups of trifluoromethyl and pyridine facilitated the amide bond cleavage and led to the in vivo formation of a carboxylic acid and an amine.

Topics: Adolescent; Adult; Aged; Aminopyridines; Antineoplastic Agents; Benzamides; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Middle Aged; Molecular Structure; Protein Kinase Inhibitors; Young Adult