| CAS |
No.956697-53-3 |
| 中文名称 |
索尼吉布 |
| 英文名称 |
Sonidegib |
| 别名 |
NVP-LDE225;索尼德吉 |
| 分子式 |
C26H26F3N3O3 |
| 分子量 |
485.5 |
| 溶解性 |
Soluble in DMSO ≥5mg/mL |
| 纯度 |
≥98% |
| 外观(性状) |
Solid |
| 储存条件 |
Powder:2-8℃，2 years;Insolvent(母液):-20℃，6 months;-80℃，1 year |
| 运输条件 |
冷藏运输 |
| EC |
EINECS 1312995-182-4 |
| MDL |
MFCD16038928 |
| SMILES |
O=C(C1=C(C)C(C(C=C2)=CC=C2OC(F)(F)F)=CC=C1)NC3=CC=C(N=C3)N4C[C@@H](C)O[C@@H](C)C4 |
| InChIKey |
VZZJRYRQSPEMTK-CALCHBBNSA-N |
| InChI |
InChI=1S/C26H26F3N3O3/c1-16-14-32(15-17(2)34-16)24-12-9-20(13-30-24)31-25(33)23-6-4-5-22(18(23)3)19-7-10-21(11-8-19)35-26(27,28)29/h4-13,16-17H,14-15H2,1-3H3,(H,31,33)/t16-,17+ |
| PubChem CID |
24775005 |
| 靶点 |
Smo |
| 通路 |
Hedgehog;Stem Cells |
| 背景说明 |
Sonidegib是有效,选择性的 Smo 拮抗剂。 |
| 生物活性 |
Sonidegib (Erismodegib) is a potent and selective Smo antagonist with IC50 of 1.3 nM and 2.5 nM for mouse and human Smo in binding assay， respectively.[1-2] |
| IC50 |
IC50: 1.3 nM (mSmo)， 2.5 nM (hSmo)[1] |
| In Vitro |
The IC50 values for Sonidegib (NVP-LDE225) for the major human CYP450 drug metabolizing enzymes is greater than 10 μM[1]. Sonidegib (LDE225)， a small molecule， clinically investigated SMO inhibitor， used alone and in combination with Nilotinib， inhibits the Hh pathway in CD34+ chronic phase (CP)-chronic myeloid leukaemia (CML) cells， reducing the number and self-renewal capacity of CML leukaemia stem cell (LSC). Sonidegib interacts directly with SMO， in a similar fashion to cyclopamine， to reduce expression of downstream Hh signaling targets. Primary CD34+ CP-CML cells are cultured in serum free media (SFM)±Sonidegib for 6， 24 and 72 hours (h). At 72 h， while there is variability between the biological samples， GLI1 is significantly downregulated following exposure to Sonidegib (10 nM; 0.78-fold and 100 nM; 0.73-fold， respectively (p[2]. |
| In Vivo |
Sonidegib (NVP-LDE225) is a weak base with a measured pKa of 4.2 and exhibits relatively poor aqueous solubility. In the subcutaneous Ptch+/-p53-/- medulloblastoma allograft mouse model， Sonidegib demonstrates dose-related antitumor activity after 10 days of oral administration of a suspension of the diphosphate salt. At a dose of 5 mg/kg/day qd， Sonidegib significantly inhibits tumor growth， corresponding to a T/C value of 33% (p[1]. Bone marrow cells and spleen cells from a subset of treated mice are transplanted into secondary recipient mice. Transplantation of either bone marrow (BM) or spleen cells from mice treated with Sonidegib (LDE225)+Nilotinib results in reduced white cell count (WCC) and reduces leukaemia development in secondary recipients compared to Sonidegib or Nilotinib alone[2]. |
| 细胞实验 |
CD34+ CP-CML cells are seeded in SFM alone±Sonidegib±Nilotinib and cultured for 24-72 h prior to assessment. Proliferation is measured using colorimetric assessment of BrDU incorporation. Proportion of viable cells versus those in early and late apoptosis is assessed by flow cytometry using annexin V-FITC and 7-amino-actinomycin D (7-AAD， Via-Probe solution). Cell cycle status is assessed using Ki67 (FITC) expression and 7-AAD incorporation. |
| 动物实验 |
Mice[2]The transgenic EGFP+/SCLtTA/TRE-BCR-ABL mouse model is used to investigate the effect of Sonidegib treatment on CML LSC in vivo. Scl-tTa-BCR-ABL mice in the FVB/N background are crossed with transgenic GFP-expressing mice. Bone marrow cells are obtained 4 weeks post induction， GFP+ cells are selected by flow cytometry and transplanted by tail vein injection (106 cells/mouse) into wild-type FVB/N recipient mice， irradiated at 900 cGy， generating a large cohort of mice with similar time of onset of leukemia. Blood samples obtained 4 weeks post transplantation confirmed a neutrophilic leukocytosis in recipient mice. Mice are treated with Nilotinib (50 mg/kg by gavage， daily)， Sonidegib (80 mg/kg by gavage， daily)， Sonidegib+Nilotinib， or with vehicle alone (control). After 3 weeks of treatment， animals are euthanised and marrow content of femurs and tibiae， spleen cells and blood obtained. Total white cell count (WCC)， GFP-expressing WCC， myeloid cells， and GFP+ progenitors and stem cells are measured by flow cytometry. Survival is assessed in a subset of mice for 120d post discontinuation of treatment. Spleen and BM cells from a subset of mice in each arm are pooled and 5×106 cells/mouse (8 mice/condition) are transplanted into wild-type FVB/N recipient mice irradiated at 900 cGy. Engraftment is monitored by drawing peripheral blood (PB) every 4 weeks. The percentage of GFP+ cells in PB is analyzed by flow cytometry. |
| 数据来源文献 |
[1]. Pan S， et al. Discovery of NVP-LDE225， a Potent and Selective Smoothened Antagonist. ACS Med Chem Lett. 2010 Mar 16;1(3):130-4.
[2]. Irvine DA， et al. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia. Sci Rep. 2016 May 9;6:25476. |
| 规格 |
5mg 10mg 25mg 50mg 100mg |
| 单位 |
瓶 |
中文
英语
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