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PTC596 Sale

(Synonyms: PTC596) 目录号 : GC38592

A BMI1 inhibitor

PTC596 Chemical Structure

Cas No.:1610964-64-1

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1mg
¥926.00
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5mg
¥2,700.00
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¥4,140.00
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¥6,120.00
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¥8,955.00
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100mg
¥15,043.00
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产品描述

PTC-596 is an inhibitor of B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), which is a member of the polycomb repressive complex 1 (PRC1) that has a role in gene silencing.1,2 It inhibits proliferation of MOLM-13 acute myeloid leukemia (AML) and Rec-1 mantle cell lymphoma (MCL) cancer cells (IC50s = 22.4 and 136 nM, respectively). It also induces BMI1 degradation in, and apoptosis of, the same cells. PTC-596 reduces microtubule polymerization and induces cell cycle arrest at the G2/M phase in MM.1S multiple myeloma cells.3 It decreases the number of side population cells, a unique cell population with stem-like characteristics, in Rec-1 cells (IC50 = 138 nM).2 PTC-596 (5 mg/kg, p.o.) increases survival in a MOLM-13 mouse xenograft model.1

1.Nishida, Y., Maeda, A., Kim, M.J., et al.The novel BMI-1 inhibitor PTC596 downregulates MCL-1 and induces p53-independent mitochondrial apoptosis in acute myeloid leukemia progenitor cellsBlood Cancer J.7(2)e527(2017) 2.Maeda, A., Nishida, Y., Weetall, M., et al.Targeting of BMI-1 expression by the novel small molecule PTC596 in mantle cell lymphomaOncotarget.9(47)28547-28560(2018) 3.Nagai, Y., Mimura, N., Rizq, O., et al.The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cellsSci. Rep.11(1)2074(2021)

Chemical Properties

Cas No. 1610964-64-1 SDF
别名 PTC596
Canonical SMILES NC1=C(F)C(NC2=CC=C(C(F)(F)F)C=C2)=NC(N3C4=CC(F)=CC=C4N=C3C)=N1
分子式 C19H13F5N6 分子量 420.34
溶解度 DMF: 30 mg/ml,DMSO: 30 mg/ml,Ethanol: 5 mg/ml 储存条件 Store at -20°C
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1 mg 5 mg 10 mg
1 mM 2.379 mL 11.8951 mL 23.7903 mL
5 mM 0.4758 mL 2.379 mL 4.7581 mL
10 mM 0.2379 mL 1.1895 mL 2.379 mL
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Research Update

Preclinical and Early Clinical Development of PTC596, a Novel Small-Molecule Tubulin-Binding Agent

Mol Cancer Ther 2021 Oct;20(10):1846-1857.PMID:34315764DOI:10.1158/1535-7163.MCT-20-0774.

PTC596 is an investigational small-molecule tubulin-binding agent. Unlike other tubulin-binding agents, PTC596 is orally bioavailable and is not a P-glycoprotein substrate. So as to characterize PTC596 to position the molecule for optimal clinical development, the interactions of PTC596 with tubulin using crystallography, its spectrum of preclinical in vitro anticancer activity, and its pharmacokinetic-pharmacodynamic relationship were investigated for efficacy in multiple preclinical mouse models of leiomyosarcomas and glioblastoma. Using X-ray crystallography, it was determined that PTC596 binds to the colchicine site of tubulin with unique key interactions. PTC596 exhibited broad-spectrum anticancer activity. PTC596 showed efficacy as monotherapy and additive or synergistic efficacy in combinations in mouse models of leiomyosarcomas and glioblastoma. PTC596 demonstrated efficacy in an orthotopic model of glioblastoma under conditions where temozolomide was inactive. In a first-in-human phase I clinical trial in patients with cancer, PTC596 monotherapy drug exposures were compared with those predicted to be efficacious based on mouse models. PTC596 is currently being tested in combination with dacarbazine in a clinical trial in adults with leiomyosarcoma and in combination with radiation in a clinical trial in children with diffuse intrinsic pontine glioma.

Pharmacokinetics and Safety of PTC596, a Novel Tubulin-Binding Agent, in Subjects With Advanced Solid Tumors

Clin Pharmacol Drug Dev 2021 Aug;10(8):940-949.PMID:33440067DOI:10.1002/cpdd.904.

PTC596 is a novel, orally bioavailable, small-molecule tubulin-binding agent that reduces B-cell-specific Moloney murine leukemia virus insertion site 1 activity and is being developed for the treatment of solid tumors. A phase 1, open-label, multiple-ascending-dose study was conducted to evaluate the pharmacokinetics and safety of the drug in subjects with advanced solid tumors. PTC596 was administered orally biweekly based on body weight. Dose escalation followed a modified 3 + 3 scheme using doses of 0.65, 1.3, 2.6, 5.2, 7.0, and 10.4 mg/kg. Following oral administration, PTC596 was rapidly absorbed, and between 0.65 and 7.0 mg/kg reached a maximum plasma concentration 2 to 4 hours after dosing. Area under the plasma concentration-time curve increased proportionally with body weight-adjusted doses. Maximum plasma concentration increased with dose, although the increase was less than dose proportional at dose levels >2.6 mg/kg. No accumulation occurred after multiple administrations up to 7.0 mg/kg. PTC596 had a terminal half-life ranging 12 to 15 hours at all doses except for the highest dose of 10.4 mg/kg, where the half-life was approximately 20 hours. Overall, PTC596 was well tolerated. The most frequently reported PTC596-related treatment-emergent adverse events were mild to moderate gastrointestinal symptoms, including diarrhea (54.8%), nausea (45.2%), vomiting (35.5%), and fatigue (35.5%). Only 1 patient treated with 10.4 mg/kg experienced dose-limiting toxicity of neutropenia and thrombocytopenia, both of which were reversible. Stable disease as best overall response was observed among 7 patients, with 2 patients receiving the study drug up to 16 weeks. These results support the further development of PTC596 for the treatment of solid tumors.

BMI1-Inhibitor PTC596 in Combination with MCL1 Inhibitor S63845 or MEK Inhibitor Trametinib in the Treatment of Acute Leukemia

Cancers (Basel) 2021 Feb 2;13(3):581.PMID:33540760DOI:10.3390/cancers13030581.

Purpose: Prognosis for acute myeloid leukemia (AML) patients is poor, particularly in TP53 mutated AML, secondary, relapsed, and refractory AML, and in patients unfit for intensive treatment, thus highlighting an unmet need for novel therapeutic approaches. The combined use of compounds targeting the stem cell oncoprotein BMI1 and activating the tumor suppressor protein p53 may represent a promising novel treatment option for poor risk AML patients. Experimental design: The BMI1 inhibitor PTC596, MCL1 inhibitor S63845, and MEK inhibitor trametinib, as well as the p53 activator APR-246 were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells. AML cells represented all major morphologic and molecular subtypes including FLT3-ITD and FLT3 wild type, NPM1 mutant and wild type, as well as TP53 mutant and wild type AML cell lines and a variety of patient derived AML cells. Results: AML cell lines were variably susceptible to PTC596 and to combination treatments with PTC596 and MCL1 inhibitor S63845, MEK inhibitor trametinib, or TP53 activator APR-246, independent of TP53 mutational status. Susceptibility of patient samples for PTC596 in combination with S63845 or trametinib was significant for the majority of adverse risk primary and secondary AML with minimal efficacy in favorable risk AML, and correlated significantly with CD34 positivity of the samples. BMI1 and MN1 gene expression, and MCL1 and MEK1 protein levels were identified as biomarkers for response to PTC596 combination treatments. Conclusions: The combination of PTC596 and S63845 may be an effective treatment in CD34+ adverse risk AML with elevated MN1 gene expression and MCL1 protein levels, while PTC596 and trametinib may be more effective in CD34+ adverse risk AML with elevated BMI1 gene expression and MEK protein levels.

The combination of the tubulin binding small molecule PTC596 and proteasome inhibitors suppresses the growth of myeloma cells

Sci Rep 2021 Jan 22;11(1):2074.PMID:33483574DOI:10.1038/s41598-021-81577-x.

The novel small molecule PTC596 inhibits microtubule polymerization and its clinical development has been initiated for some solid cancers. We herein investigated the preclinical efficacy of PTC596 alone and in combination with proteasome inhibitors in the treatment of multiple myeloma (MM). PTC596 inhibited the proliferation of MM cell lines as well as primary MM samples in vitro, and this was confirmed with MM cell lines in vivo. PTC596 synergized with bortezomib or carfilzomib to inhibit the growth of MM cells in vitro. The combination treatment of PTC596 with bortezomib exerted synergistic effects in a xenograft model of human MM cell lines in immunodeficient mice and exhibited acceptable tolerability. Mechanistically, treatment with PTC596 induced cell cycle arrest at G2/M phase followed by apoptotic cell death, associated with the inhibition of microtubule polymerization. RNA sequence analysis also revealed that PTC596 and the combination with bortezomib affected the cell cycle and apoptosis in MM cells. Importantly, endoplasmic reticulum stress induced by bortezomib was enhanced by PTC596, providing an underlying mechanism of action of the combination therapy. Our results indicate that PTC596 alone and in combination with proteasome inhibition are potential novel therapeutic options to improve outcomes in patients with MM.

Off-target effect of the BMI1 inhibitor PTC596 drives epithelial-mesenchymal transition in glioblastoma multiforme

NPJ Precis Oncol 2020 Jan 6;4:1.PMID:31934644DOI:10.1038/s41698-019-0106-1.

Glioblastoma multiforme (GBM) is an incurable primary brain tumor containing a sub-population of cancer stem cells (CSCs). Polycomb Repressive Complex (PRC) proteins BMI1 and EZH2 are enriched in CSCs, promoting clonogenic growth and resistance to genotoxic therapies. We report here that when used at appropriate concentrations, pharmaceutical inhibitors of BMI1 could efficiently prevent GBM colony growth and CSC self-renewal in vitro and significantly extend lifespan in terminally ill tumor-bearing mice. Notably, molecular analyses revealed that the commonly used PTC596 molecule targeted both BMI1 and EZH2, possibly providing beneficial therapeutic effects in some contexts. On the other hand, treatment with PTC596 resulted in instant reactivation of EZH2 target genes and induction of a molecular program of epithelial-mesenchymal transition (EMT), possibly explaining the modified phenotype of some PTC596-treated tumors. Treatment with a related but more specific BMI1 inhibitor resulted in tumor regression and maintenance of cell identity. We conclude that inhibition of BMI1 alone is efficient at inducing GBM regression, and that dual inhibition of BMI1 and EZH2 using PTC596 may be also beneficial but only in specific contexts.