治疗ESR1突变药物再整理

一、Bazedoxifene 巴多昔芬
; d# ]8 T* q8 \9 {- P巴多昔芬 Bazedoxifene (TSE-424) 是一种有口服活性的，能透过血脑屏障的，非甾体、选择性的雌激素受体调节剂 (SERM)，对 ERα 和 ERβ 作用的 IC50 值分别为 26 nM 和 99 nM。
* S+ y6 J. K# d' x/ B2 g: _- v0 q1、CAS号：198481-32-2
2、分子量：470.6
3、用法用量：：每天一次，每次40毫克。“All patients received bazedoxifene 40 mg orally once daily ”《Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor-Positive Breast Cancer》） 需要注意的是，目前有巴多昔芬成品药卖，是治疗骨质疏松的，剂量是每天20毫克，跟抗癌剂量是不一样的。
7 N/ c& N  K0 L) w" a4、常见副作用：血栓、恶心、疲劳、关节痛、潮热
- }, p9 \9 E& T2 l2 _5、对ESR1 Y537S：有效。（“We found that BZA possesses improved inhibitory potency against the Y537S and D538G ERα mutants compared to tamoxifen”“comprehensive biophysical and structural biology studies show BZA's selective estrogen receptor degrading (SERD) properties that override the stabilizing effects of the Y537S and D538G ERα mutations.”《The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells》）
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二、Lasofoxifene 拉索昔芬
7 S7 u! s  b/ u拉索昔芬 Lasofoxifene (CP-336156) 是一种具有口服活性和选择性的雌激素受体调节剂 (SERM)，对 ERα 的 IC50 值 1.5nm。
1、CAS号：180916-16-9
  M* B% `+ B* o1 `) n4 d. |9 N2、分子量：413.55
: ?. g4 ^- x  d% u: R& T3、用法用量：每天一次，一次5毫克（“oral lasofoxifene 5 mg daily”《Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial》）
4、常见副作用：血栓、恶心、疲劳、关节痛、潮热
5、对ESR1 Y537S：有效。（“lasofoxifene stabilizes an antagonist conformation of both wild-type and Y537S LBD. The ability of lasofoxifene to promote an antagonist conformation of Y537S, combined with its long half-life and bioavailability, likely contributes to the observed potent inhibition of primary tumor growth and metastasis of MCF7 Y537S cells.”《Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer》）

三、Elacestrant 艾拉司群
% T3 d$ y2 f8 Y0 F# X- e) aElacestrant (RAD1901) 是一种具有口服活性的选择性 estrogen receptor (ER) 降解剂 (SERD)，对 ERα 和 ERβ 的 IC50 值分别为 48 和 870 nM。
1、CAS号：722533-56-4
/ l0 v; o9 ^. F9 ]- ^3 F6 K# a2、分子量：458.63
3、用法用量：艾拉司群的推荐剂量345mg，每日服用一次，需要与食物一起服用，每天尽量大约在同一时间服用。
4、常见副作用：肌肉骨骼疼痛、恶心、胆固醇升高、疲劳、血红蛋白减少、呕吐、钠减少、肌酐增加、食欲下降、腹泻、头痛、便秘、腹痛、潮热、消化不良等。
6 @7 |6 i, `' ]) j5 m5、对ESR1 Y537S：有效。（“Finally, elacestrant demonstrated antitumor activity in models resistant to CDK4/6 inhibitors and fulvestrant, including those harboring the commonly detected ESR1 mutations Y537S and D538G .”《《EMERALD: Phase III Trial of Elacestrant (RAD1901) vs Endocrine Therapy for Previously Treated ER+ Advanced Breast Cancer》》）
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4 e8 M$ O4 F, X8 q% A! h3 O) S+ z. b四、AZD9496
ZD9496 是有效,选择性的雌激素受体 (ERα) 拮抗剂，IC50 为 0.28 nM。
1、CAS 号：1639042-08-2。
7 B; p5 M5 B' u* u* a2、分子量：442.47。
* A  _- F- i1 d3、用法用量：每天两次，每次250毫克。（“Based on the clinical activity and the safety and tolerability profile of AZD9496 at the 250 mg BID dose, this was selected as the recommended dose for the subsequent AZD9496 study.”《A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2− Advanced Breast Cancer》）
4、常见副作用：恶心、腹泻、疲劳、上腹痛、转氨酶升高
5、对ESR1 Y537S：有效。（“tumors driven by Y537S, but not D5358G, E380Q, or S463P, were less effectively inhibited by fulvestrant than more potent and bioavailable antagonists, including AZD9496. ”《Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists》）