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Olverembatinib Sale

(Synonyms: GZD824; HQP1351) 目录号 : GC62207

A Bcr/Abl inhibitor

Olverembatinib Chemical Structure

Cas No.:1257628-77-5

规格 价格 库存 购买数量
10mM (in 1mL DMSO)
¥656.00
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5mg
¥560.00
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10mg
¥910.00
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25mg
¥1,890.00
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50mg
¥3,010.00
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100mg
¥4,760.00
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产品描述

GZD-824 is an orally available inhibitor of a broad spectrum of Bcr/Abl tyrosine kinase mutants including T315I (IC50s = 0.34 and 0.68 nM for wild-type Bcr/Abl and Bcr/AblT315I, respectively).1 It has been shown to suppress the proliferation of Bcr/Abl-positive K562 and Ku812 human chronic myelogenous leukemia cells (IC50s = 0.2 and 0.13 nM, respectively) and induce tumor regression in mouse xenograft tumor models driven by either wild-type or mutant Bcr/Abl.1

1.Ren, X., Pan, X., Zhang, Z., et al.Identification of GZD824 as an orally bioavailable inhibitor that targets phosphorylated and nonphosphorylated breakpoint cluster region-Abelson (Bcr-Abl) kinase and overcomes clinically acquired mutation-induced resistance against imatinibJ. Med. Chem.56(3)879-894(2013)

Chemical Properties

Cas No. 1257628-77-5 SDF
别名 GZD824; HQP1351
分子式 C29H27F3N6O 分子量 532.56
溶解度 DMSO : ≥ 100 mg/mL (187.77 mM) 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 1.8777 mL 9.3886 mL 18.7772 mL
5 mM 0.3755 mL 1.8777 mL 3.7554 mL
10 mM 0.1878 mL 0.9389 mL 1.8777 mL
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Research Update

Olverembatinib: First Approval

Drugs 2022 Mar;82(4):469-475.PMID:35195876DOI:10.1007/s40265-022-01680-9.

Olverembatinib (HQP1351) is an oral, third-generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by Ascentage Pharma for the treatment of chronic myeloid leukaemia (CML), acute myeloid leukaemia, acute lymphoblastic leukaemia (ALL) and solid tumours, including gastrointestinal stromal tumours (GIST). Olverembatinib is an ATP binding-site inhibitor of wild type BCR-ABL1 kinase and a broad spectrum of BCR-ABL1 mutants, including mutant T315I, which confers resistance against all first- and second-generation TKIs. In November 2021, Olverembatinib received its first approval in China for the treatment of adult patients with TKI-resistant chronic-phase CML (CML-CP) or accelerated-phase CML (CML-AP) harbouring the T315I mutation, as confirmed by a validated diagnostic test. Clinical studies are underway in the US for CML and precursor cell ALL, and in China for solid tumours, including GIST. This article summarizes the milestones in the development of Olverembatinib leading to this first approval for the treatment of CML-CP or CML-AP.

Olverembatinib (HQP1351), a well-tolerated and effective tyrosine kinase inhibitor for patients with T315I-mutated chronic myeloid leukemia: results of an open-label, multicenter phase 1/2 trial

J Hematol Oncol 2022 Aug 18;15(1):113.PMID:35982483DOI:10.1186/s13045-022-01334-z.

Background: BCR-ABL1T315I mutations confer resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML). Olverembatinib is a new potent BCR-ABL1 TKI with preclinical activity against T315I-mutated CML. In phase 1/2 studies, we explored the safety and efficacy of Olverembatinib in Chinese adults with TKI-resistant CML in the chronic phase (CML-CP) and accelerated phase (CML-AP). Methods: In the phase 1 study, Olverembatinib was orally administered once every other day in 28-day cycles at 11 dose cohorts ranging from 1 to 60 mg, and we evaluated the maximum tolerated dose, recommended phase 2 dose (RP2D), safety, efficacy, and pharmacokinetics of Olverembatinib. In the phase 2 studies, Olverembatinib was administered at the RP2D of 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response by the end of Cycle 12 in CML-CP and CML-AP, respectively. Fine and Gray's hazard models were used to identify covariates associated with responses. Results: A total of 165 patients (> 80.0% of whom had received ≥ 2 TKIs) were enrolled in this study. Among 127 patients with CML-CP, the 3-year cumulative incidences of achieving MCyR, complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0, and MR4.5 were 79.0, 69.0, 56.0, 44.0 and 39.0%, respectively. The highest response rates were observed in patients with a single T315I mutation. Among 38 patients with CML-AP, the 3-year cumulative incidences of achieving MCyR, CCyR, MMR, MR4.0, and MR4.5 were 47.4%, 47.4%, 44.7%, 39.3%, and 32.1%, respectively. In multivariate analyses, baseline BCR-ABL1 mutation status was significantly associated with cytogenetic and molecular responses. Common treatment-related adverse events included skin hyperpigmentation, hypertriglyceridemia, proteinuria, and severe thrombocytopenia. Conclusions: Olverembatinib was well tolerated, with significant antileukemic activity in adults with TKI-resistant CML-CP and CML-AP, especially those with the T315I mutation. Trial registration: The phase 1 trial is registered at CTR20220566, and the two single-arm, open-label phase 2 studies are registered at ClinicalTrials.gov: NCT03883087 (CML-CP) and NCT03883100 (CML-AP).

Olverembatinib in chronic myeloid leukemia

Drugs Today (Barc) 2022 Nov;58(11):531-538.PMID:36422514DOI:10.1358/dot.2022.58.11.3441854.

The introduction of tyrosine kinase inhibitors (TKIs) represents a new era in the management of chronic myeloid leukemia (CML). Despite their long clinical success, point mutations emerging before or during TKI treatment remain an obstacle for several cases. T315I is one of these point mutations in the tyrosine kinase domain of BCR::ABL1. It is a major cause of resistance against first- and second-generation TKIs and therefore lowers survival rates of a small group of patients. Olverembatinib (HQP-1351, formerly GZD-824) is a novel, orally active TKI, which acts through targeting the ATP-binding site of the BCR::ABL1 tyrosine kinase. In recent studies, Olverembatinib appears to be an effective and safe treatment option for CML patients harboring T315I mutation. This article mainly focuses on the efficacy and safety data of Olverembatinib along with other clinically available and potentially active drugs against T315I-mutated CML.

Chronic myeloid leukemia: 2022 update on diagnosis, therapy, and monitoring

Am J Hematol 2022 Sep;97(9):1236-1256.PMID:35751859DOI:10.1002/ajh.26642.

Disease overview: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100 000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. Diagnosis: CML is characterized by a balanced genetic translocation, t (9;22) (q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR::ABL1 fusion oncogene, which in turn translates into a BCR::ABL1 oncoprotein. Frontline therapy: Four tyrosine kinase inhibitors (TKIs), imatinib, dasatinib, bosutinib, and nilotinib are approved by the United States Food and Drug Administration for first-line treatment of newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses but had no impact on survival prolongation, likely because of the availability of effective TKIs salvage therapies for patients who have a cytogenetic relapse with frontline TKI therapy. Salvage therapy: For CML post failure on frontline therapy, second-line options include second and third generation TKIs. Although potent and selective, these TKIs exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR::ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib, asciminib, and Olverembatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP and failure (due to resistance) of at least two TKIs, and for all patients in advanced phase disease. Older patients who have a cytogenetic relapse post failure on all TKIs can maintain long-term survival if they continue a daily most effective/least toxic TKI, with or without the addition of non-TKI anti-CML agents (hydroxyurea, omacetaxine, azacitidine, decitabine, cytarabine, busulfan and others).

Olverembatinib inhibits SARS-CoV-2-Omicron variant-mediated cytokine release in human peripheral blood mononuclear cells

EMBO Mol Med 2022 Jun 8;14(6):e15919.PMID:35579119DOI:10.15252/emmm.202215919.

The N-terminus domain (NTD) of the SARS-CoV-2 Omicron variant spike protien strongly induces multiple inflammatory molecules in human peripheral blood mononuclear cells, unaffected by the mutations observed in the NTD. Olverembatinib, a clinical-stage multi-kinase inhibitor, potently inhibits Omicron NTD-mediated cytokine release.