伊立替康、索拉非尼与quinacrine的其他靶点

药物都是多靶点的，药物的“常用”靶点未必是它结合亲和力最高的靶点，也未必是它的最佳的靶点；这个靶点之所以成为“常用”，很多时候只不过是因为这个靶点发现的比较早而已。

% Y7 i# Q; J4 X5 ~( L0 P6 D- K一、伊立替康
7 J/ H$ r( K8 s! N* Y) G& HIrinotecan 伊立替康目前常用靶点是top1。

1、伊立替康与mdm2和bcl-xl的结合亲和力，超过与top1的结合亲和力
《A novel mechanism of irinotecan targeting MDM2 and Bcl-xL》
; W- S/ O2 ?  I3 o- yIn addition, docking simulations of Irinotecan further supported that it binds more stably to MDM2 and Bcl-xL than to Topo I based on the energy values: 100.37, 170.59 and 99.53 respectively.
1 y$ y, ^7 G. @& B9 W  ~7 S$ XMDM2目前尚无专门靶向药上市，伊立替康完全可以当做mdm2抑制剂一用。

8 c7 Z; {5 l! r: s+ b6 x! N5 G) D& p有位乳腺癌病友mdm2高倍扩增，用了伊立替康脂质体是有效的。耐药后再去做基因检测，mdm2扩增已经没有了。

( b4 k8 @- h; i9 n2 N5 s" H8 h  f2、伊立替康与her2的结合亲和力，超过拉帕替尼。
《Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2》
7 y% G/ A& d( z& d$ b% e8 U& FHER2-ligand complexes showed that irinotecan (−56.4 ± 5 kcal/mol), quinacrine (−54.9 ± 3 kcal/mol), alfuzosin (−51.9 ± 6 kcal/mol), and antrafenine (−51.1 ± 3 kcal/mol) showed the highest binding free energy for HER2. The affinity of irinotecan and quinacrine was higher than that reported between HER2 and lapatinib (−51 ± 4 kcal/mol) [10] and gefitinib (−26 ± 6.0) .
+ C8 G9 U' U" z伊立替康与her2的结合亲和力，超过拉帕替尼。伊立替康是静脉注射药，剂型上也有了脂质体这种比较好的剂型，生物利用度上肯定是超过口服剂型的拉帕替尼的。合理推测，伊立替康治疗her2过表达的疗效不会劣于拉帕替尼。
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二、索拉非尼
索拉非尼是Raf-1和B-Raf的多重激酶抑制剂，无细胞试验中IC50分别为6 nM和22 nM。索拉非尼 还可抑制VEGFR-2、VEGFR-3、PDGFR-β、Flt-3和c-KIT，对应的IC50值分别为90 nM、20 nM、57 nM、59 nM和68 nM。索拉非尼 可诱导autophagy、apoptosis并激活ferroptosis。

0 x! n1 m+ q+ j3 J$ s/ C1、索拉非尼抑制ccnd1
《索拉非尼通过下调细胞周期蛋白D1诱导急性髓细胞白血病细胞凋亡的实验研究》
- F  s/ @- P. W6 i7 f3 P“将加有索拉非尼的细胞培养组设为实验组”。“定量PCR测定实验组CCND1表达下调达5.88倍”
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1 }3 `0 l" z- p: J; |. p) y: W0 U0 T2、有FGF3/4/19系列基因扩增，用索拉非尼获益可能性大
（1）《FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma》
A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P = 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P = 0.006) and a poorly differentiated histological type (5/13, P = 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3.
（2）《Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment》
The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification.
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乳腺癌和食管癌里，ccnd1扩增和FGF3/4/19系列基因扩增经常同时出现。常规用法是用cdk4/6抑制剂针对治疗ccnd1扩增，用乐伐替尼、厄达替尼等药物针对治疗FGF3/4/19系列基因扩增。现在也可以考虑用索拉非尼同时针对治疗ccnd1扩增和FGF3/4/19系列基因扩增。
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9 f; I/ Q( V2 e三、Quinacrine
* P% N# B+ w% Oquinacrine是一种治疗疟疾的老药。
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. [7 i( j: a; c; ]3 z1、quinacrine 与her2的结合亲和力，超过拉帕替尼
& \6 j  t, P4 G( Q' N/ ^  e《Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2》
% l- U2 H* ?. B2 ^7 KHER2-ligand complexes showed that irinotecan (−56.4 ± 5 kcal/mol), quinacrine (−54.9 ± 3 kcal/mol), alfuzosin (−51.9 ± 6 kcal/mol), and antrafenine (−51.1 ± 3 kcal/mol) showed the highest binding free energy for HER2. The affinity of irinotecan and quinacrine was higher than that reported between HER2 and lapatinib (−51 ± 4 kcal/mol) [10] and gefitinib (−26 ± 6.0) .

2、quinacrine抑制 hsp90、top2
《Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy》
, `3 f* q8 t$ i) s* ]“Our study identified quinacrine as a potential dual-target inhibitor of Topo II and Hsp90”
quinacrine抑制her2、top2，her2扩增患者可以把它作为8201耐药的辅助用药。
Quinacrine dihydrochloride，分子量 472.88，应该可以入脑。

3 I# Z. x8 [! o  S9 y7 V$ J2 H3、quinacrine抗癌，做过一些临床试验
（1）《Phase I study of the combination of quinacrine and erlotinib in patients with locally advanced or metastatic non small cell lung cancer》
; J1 S8 p0 h% x* G1 [“The dose of 50 mg of quinacrine every other day ”
$ }# J) I( i5 `" A- p（2）《First-in-Human Phase 1b Trial of Quinacrine Plus Capecitabine in Patients With Refractory Metastatic Colorectal Cancer》
“quinacrine 100 mg by mouth twice daily on days 1-21 of a 21-day cycle in mCRC patients.”