3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide has been researched along with Leukemia--Myelogenous--Chronic--BCR-ABL-Positive* in 5 studies

Reviews

1 review(s) available for 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

ArticleYear
The Dawn of Allosteric BCR-ABL1 Drugs: From a Phenotypic Screening Hit to an Approved Drug.
    Journal of medicinal chemistry, 2022, 06-09, Volume: 65, Issue:11

    Chronic myeloid leukemia (CML) is driven by the constitutive activity of the BCR-ABL1 fusion oncoprotein. Despite the great success of drugs that target the BCR-ABL1 ATP-binding site in transforming CML into a manageable disease, emerging resistance point mutations impair inhibitor binding, thereby limiting the effectiveness of these drugs. Recently, allosteric inhibitors that interact with the ABL1 myristate-binding site have been shown to awaken an endogenous regulatory mechanism and reset full-length BCR-ABL1 into an inactive assembled state. The discovery and development of these allosteric inhibitors demonstrates an in-depth understanding of the fundamental regulatory mechanisms of kinases. In this review, we illustrate the structural basis of c-ABL1's dynamic regulation of autoinhibition and activation, discuss the discovery of allosteric inhibitors and the characterization of their mechanism of action, present the therapeutic potential of dual binding to delay the development of mutation-driven acquired resistance, and suggest key lessons learned from this program.

    Topics: Binding Sites; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Protein Kinase Inhibitors

2022

Other Studies

4 other study(ies) available for 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

ArticleYear
Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1.
    Journal of medicinal chemistry, 2018, 09-27, Volume: 61, Issue:18

    Chronic myelogenous leukemia (CML) arises from the constitutive activity of the BCR-ABL1 oncoprotein. Tyrosine kinase inhibitors (TKIs) that target the ATP-binding site have transformed CML into a chronic manageable disease. However, some patients develop drug resistance due to ATP-site mutations impeding drug binding. We describe the discovery of asciminib (ABL001), the first allosteric BCR-ABL1 inhibitor to reach the clinic. Asciminib binds to the myristate pocket of BCR-ABL1 and maintains activity against TKI-resistant ATP-site mutations. Although resistance can emerge due to myristate-site mutations, these are sensitive to ATP-competitive inhibitors so that combinations of asciminib with ATP-competitive TKIs suppress the emergence of resistance. Fragment-based screening using NMR and X-ray yielded ligands for the myristate pocket. An NMR-based conformational assay guided the transformation of these inactive ligands into ABL1 inhibitors. Further structure-based optimization for potency, physicochemical, pharmacokinetic, and drug-like properties, culminated in asciminib, which is currently undergoing clinical studies in CML patients.

    Topics: Allosteric Regulation; Animals; Dogs; Drug Discovery; Fusion Proteins, bcr-abl; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mice; Models, Molecular; Molecular Structure; Mutation; Niacinamide; Phosphorylation; Protein Conformation; Protein Kinase Inhibitors; Pyrazoles; Rats; Rats, Sprague-Dawley; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

2018
Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.
    Nature, 2010, Jan-28, Volume: 463, Issue:7280

    In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

    Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Binding Sites; Bone Marrow Transplantation; Cell Line, Tumor; Crystallization; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Inhibitory Concentration 50; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Mass Spectrometry; Mice; Models, Molecular; Mutation; Piperazines; Protein Structure, Tertiary; Pyrimidines; Transplantation, Heterologous

2010
Dual Src and Abl inhibitors target wild type Abl and the AblT315I Imatinib-resistant mutant with different mechanisms.
    Bioorganic & medicinal chemistry, 2010, Jun-01, Volume: 18, Issue:11

    The tyrosine kinase Src and its close homolog Abl, both play important roles in chronic myelogenous leukemia (CML) progression and Imatinib resistance. No clinically approved inhibitors of the drug-resistant AblT315I exist to date. Here, we present a thorough kinetic analysis of two potent dual Src-Abl inhibitors towards wild type Src and Abl, and the AblT315I mutant. Our results show that the most potent compound BO1 shows only a modest loss of potency (fourfold) towards the AblT315I mutant in vitro and was an ATP-competitive inhibitor of wild type Abl but it acted as a non-competitive inhibitor in the case of AblT315I.

    Topics: Adenosine Triphosphate; Benzamides; Drug Resistance, Neoplasm; Humans; Imatinib Mesylate; Kinetics; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutant Proteins; Mutation, Missense; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Pyrimidines; src-Family Kinases

2010
Allosteric inhibitors of Bcr-abl-dependent cell proliferation.
    Nature chemical biology, 2006, Volume: 2, Issue:2

    Chronic myelogenous leukemia (CML) is a myeloproliferative disorder characterized at the molecular level by the expression of Bcr-abl, a 210-kDa fusion protein with deregulated tyrosine kinase activity. Encouraged by the clinical validation of Bcr-abl as the target for the treatment of CML by imatinib, we sought to identify pharmacological agents that could target this kinase by a distinct mechanism. We report the discovery of a new class of Bcr-abl inhibitors using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library. Compounds in this class (exemplified by GNF-2) show exclusive antiproliferative activity toward Bcr-abl-transformed cells, with potencies similar to imatinib, while showing no inhibition of the kinase activity of full-length or catalytic domain of c-abl. We propose that this new class of compounds inhibits Bcr-abl kinase activity through an allosteric non-ATP competitive mechanism.

    Topics: Animals; Antineoplastic Agents; Apoptosis; Benzamides; Cell Line; Cell Line, Transformed; Cell Proliferation; Drug Resistance, Neoplasm; Fusion Proteins, bcr-abl; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mice; Piperazines; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines

2006