Ripretinib (DCC-2618) is an orally bioavailable, selective KIT and PDGFRA switch-control inhibitor. Ripretinib (DCC-2618) targets and binds to both wild-type and mutant forms of KIT and PDGFRA specifically at their switch pocket binding sites, thereby preventing the switch from inactive to active conformations of these kinases and inactivating their wild-type and mutant forms. Ripretinib (DCC-2618) also inhibits multiple other kinase targets, such as FLT3 and KDR (or VEGFR-2)[1][2]. DCC-2618 exerts antineoplastic effect and induces apoptosis[3].
IC50 & Target
PDGFRA
KIT
体外研究 (In Vitro)
Ripretinib (DCC-2618) suppresses phosphorylation of KIT and decreases the expression of phosphosphorylated (p)STAT5, pAKT and pERK1/2 in neoplastic mast cells. Ripretinib inhibits the growth of ROSAKIT K509I cells with an IC50 of 34 ± 10 nM, and also induces apoptosis in these cells. Ripretinib (0.1-1.0 μM) inhibits IgE-dependent histamine release from basophils and spontaneous tryptase release from neoplastic mast cells, and also counteracts growth and survival of leukemic monocytes and blast cells at 0.01-5 μM[2]. Ripretinib (DCC-2618) is a pan-KIT and PDGFRA inhibitor, shows cytotoxic activity against gastrointestinal stromal tumors[4].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
510.36
Formula
C24H21BrFN5O2
CAS 号
1442472-39-0
中文名称
瑞普替尼;瑞派替尼
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Schneeweiss M, et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica. 2018 May;103(5):799-809.
[2]. KIT/PDGFR Inhibitor DCC-2618.
[3]. Schneeweiss M, et al. The KIT and PDGFRA switch-control inhibitor DCC-2618 blocks growth and survival of multiple neoplastic cell types in advanced mastocytosis. Haematologica. 2018 May;103(5):799-809.
[4]. BLU-285, DCC-2618 Show Activity against GIST. Cancer Discov. 2017 Feb;7(2):121-122.
Rebastinib (DCC-2036) is an orally active, non-ATP-competitive Bcr-Abl inhibitor for Abl1WT and Abl1T315I with IC50s of 0.8 nM and 4 nM, respectively. Rebastinib also inhibits SRC, KDR, FLT3, and Tie-2, and has low activity to seen towards c-Kit.
Rebastinib potently (IC50 0.82 nM) inhibits u-ABL1native, which is thought to exist predominantly in the inactive type II conformation. In addition, Rebastinib also strongly inhibits p-ABL1native (IC50 2 nM), which more readily adopts an active, Type I conformation[1]. Rebastinib potently inhibits both u-ABL1T315I (IC50 5 nM) and p-ABL1T315I (IC50 4 nM), both of which exist predominately in the Type I conformation due to stabilization of an activating hydrophobic spine by the T315I mutation[1]. In addition to ABL1, Rebastinib also inhibits the SRC family kinases LYN, SRC, FGR, and HCK, and PDGFRα, and PDGFRβ with IC50 of 29±1, 34±6, 38±1, 40±1, 70±10 and 113±10 nM, respectively. Notably, Rebastinib spared c-KIT (IC50 481 nM)[1]. Rebastinib effectively inhibits the proliferation of Ba/F3 cells expressing native BCR-ABL1native (IC50 5.4 nM). Rebastinib also inhibits proliferation of the Ph+ cell line K562 (IC50 5.5 nM)[1]. Rebastinib also inhibits proliferation of several common TKI-resistant mutants of BCR-ABL1, including G250E, Q252H, Y235F, E255K, V299L, F317L, and M351T, at IC50s ranging from 6-150 nM. Rebastinib effectively inhibits autophosphorylation of BCR-ABL1native (IC50 29 nM) and BCR-ABL1T315I (IC50 18 nM), as well as the phosphorylation of STAT5 in both cell lines (IC50 28 nM and 13 nM, respectively)[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
A single dose of Rebastinib (DCC-2036; oral; 100 mg/kg) affords circulating plasma levels that exceeds 12 μM for up to 24 hours, and effectively inhibits BCR-ABL1 signaling for up to 8 hours in Ba/F3-BCR-ABL1T315I leukemia cells isolated from BM and spleen of tumor-bearing mice[1]. Treatment of mice bearing Ba/F3-BCR-ABL1T315I leukemia cells with Rebastinib at 100 mg/kg once daily by oral gavage significantly prolonged their survival, while STI571 at 100 mg/kg twice daily is ineffective[1]. In this aggressive allograft model, Rebastinib is as effective for treatment of BCR-ABLT315I leukemia as STI571 at 100 mg/kg twice daily in BCR-ABL1native leukemia, and reduces the leukemia cell burden in the spleens of treated mice[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
553.59
Formula
C30H28FN7O3
CAS 号
1020172-07-9
运输条件
Room temperature in continental US; may vary elsewhere.
储存方式
Powder
-20°C
3 years
4°C
2 years
In solvent
-80°C
6 months
-20°C
1 month
溶解性数据
In Vitro:
DMSO : 50 mg/mL (90.32 mM; ultrasonic and warming and heat to 80°C)
将 2 g 磺丁基醚 β-环糊精加入 5 mL 生理盐水中,再用生理盐水定容至 10 mL,完全溶解,澄清透明
*以上所有助溶剂都可在 上海金畔生物科技有限公司 网站选购。
参考文献
[1]. Chan WW, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011, 19(4), 556-568.
Cell Assay [1]
Ba/F3 cells (3×103 cells/well) or primary Ph+ leukemia cells (5×104 cells/well) are plated in triplicate in 96-well plates containing test compounds (e.g., Rebastinib (DCC-2036)). After 72h, viable cells are quantified by resazurin or MTT assay. Results represent an average of at least three independent experiments[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [1]
Mice[1] Ba/F3 cells (1×106) transformed to interleukin-3 independence by transduction with either BCR-ABL1native or BCR-ABL1T315I retrovirus are injected intravenously into syngeneic Balb/c recipients. Beginning day 3 post-injection, mice are treated with STI571 (100 mg/kg in water twice daily via oral gavage) or with Rebastinib (DCC-2036) (100 mg/kg in 0.5% CMC/1% Tween-80, once daily via oral gavage) or with vehicle (0.5% CMC/1% Tween-80) alone. For induction of CML-like leukemia, bone marrow (BM) from male Balb/c donor mice is harvested 4d after intravenous administration of 150 mg/kg 5-FU, transduced with BCR-ABL1T315I retrovirus, and 5×105 cells injected intravenously into sublethally irradiated (400 cGy) Balb/c recipients. Beginning at d5 post-transplant, cohorts are treated once daily by oral gavage with vehicle alone, or Rebastinib (DCC-2036) at 100 mg/kg. For induction of B-cell acute lymphoblastic leukemia, BM from donors not pretreated with 5-FU is transduced once with BCR-ABL1T315I retrovirus and 1×106 cells injected into sublethally irradiated Balb/c recipients. Beginning at d8 post-transplant, cohorts are treated twice daily by oral gavage with vehicle alone, with Rebastinib (DCC-2036) at 60 mg/kg, with STI571 at 100 mg/kg (in water), or with BMS-354825 at 10 mg/kg (in 80 mM citric acid pH 3.1).
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Chan WW, et al. Conformational control inhibition of the BCR-ABL1 tyrosine kinase, including the gatekeeper T315I mutant, by the switch-control inhibitor DCC-2036. Cancer Cell. 2011, 19(4), 556-568.
Vimseltinib (DCC-3014) is a c-FMS (CSF-IR) and c-Kit dual inhibitor extracted from patent WO2014145025A2, Compound Example 10, has IC50s of <0.01 μM and 0.1-1 μM, respectively[1].
Altiratinib (DCC-2701) is a multi-targeted kinase inhibitor with IC50s of 2.7, 8, 9.2, 9.3, 0.85, 4.6, 0.83 nM for MET, TIE2, VEGFR2, FLT3, Trk1, Trk2, and Trk3 respectively.
IC50 & Target[1]
VEGFR2
9.2 nM (IC50)
Trk1
0.85 nM (IC50)
Trk2
4.6 nM (IC50)
Trk3
0.93 nM (IC50)
MET
2.7 nM (IC50)
TIE2
8 nM (IC50)
FLT3
9.3 nM (IC50)
体外研究 (In Vitro)
Altiratinib also inhibits MET isoforms METD1228H, MET D1228N, METY1230C, METY1230D, METY1230H, METM1250T with IC50s of 3.6, 1.3, 1.2, 0.37, 1.5 and 6 nM, respectively. Altiratinib inhibits MET phosphorylation with IC50 values of 0.85 and 2.2 nM, respectively. In the U-87 glioblastoma cell line, MET and HGF are both expressed. Altiratinib blocks autocrine activation of MET phosphorylation in these cells (IC50=6.2 nM). Altiratinib potently inhibits cellular proliferation in MET-amplified EBC-1 and MKN-45 cells, as well as TPM3-TRKA fusion KM-12 cells. Activation of MET is known to increase the motility and invasiveness of cancer cells: Altiratinib inhibits HGF-induced A549 cell migration, with an IC50 of 13 nM. Altiratinib also inhibits FLT3-ITD mutant MV-4-11 cell proliferation with an IC50 of 12 nM[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
体内研究 (In Vivo)
A single oral dose of 30 mg/kg Altiratinib leads to >95% inhibition of MET phosphorylation for the entire 24-hour period. A single 10 mg/kg oral dose of Altiratinib exhibits complete inhibition of MET phosphorylation through 12 hours and 73% inhibition at 24 hours postdose. Altiratinib dosed at 10 mg/kg twice a day leads to a significant 90% decrease in BLI signal. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood–brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Clinical Trial
分子量
510.46
Formula
C26H21F3N4O4
CAS 号
1345847-93-9
运输条件
Room temperature in continental US; may vary elsewhere.
[1]. Smith BD, et al. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated DrugResistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther. 2015 Sep;14(9):2023-34.
Cell Assay [1]
Altiratinib is dispensed into assay plates. Cells are added to 96-well (EBC-1, M-NFS-60, and SK-MEL-28: 2,500 cells/well; MKN-45: 5,000 cells/well; MV-4-11: 10,000 cells/well) or 384-well plates (A375 and HCT-116: 625 cells/well; BT-474, KM-12, PC-3, and U-87-MG: 1,250 cells/well). Plates are incubated for 72 hours. Viable cells are quantified using resazurin using a plate reader with excitation at 540 nm and emission at 600 nm[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
Animal Administration [1]
Mice: Female nude mice are inoculated subcutaneously. On days 9 to 10, when tumor volumes reached 326 mg on average, mice are randomly assigned to groups and dosed once orally with 0.4% HMPC, (n=3); Altiratinib at 30 mg/kg (n=21); or Altiratinib at 10 mg/kg (n=21). At specified time points, whole blood and tumors are collected. Pharmacokinetic analysis is performed. Tumor samples are processed in the Western blot assay methods[1].
上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.
参考文献
[1]. Smith BD, et al. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated DrugResistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther. 2015 Sep;14(9):2023-34.