MDV3100 (Enzalutamide)
(Synonyms: 恩杂鲁胺; MDV3100) 目录号 : GC12385
MDV3100(enzalutamide) 是第二代 AR 拮抗剂，在 LNCaP 前列腺细胞中的 IC50 为 36nM。
Cas No.:915087-33-1
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| Cell experiment [1]: | |
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Cell lines |
LNCap, C4-2, PC3, DU145 and 22RV1 cell lines |
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Preparation Method |
Different concentration gradients of various compounds (MDV3100， Afatinib, Erlotinib, Sorafenib, Gefitinib) were added to each group. The control group was treated with 0.1% DMSO. The cells were continuously treated for 72h, then supplemented with 10μL MTT solution for 4h. |
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Reaction Conditions |
0-100μM |
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Applications |
MDV3100 moderately inhibited the proliferation of PC3 and DU145 cells, both of which are androgen-independent PCa cell lines. Moreover, it also inhibited proliferation in the androgen-dependent LNCap, 22RV1 and C4-2 cell lines, with IC50 values of 1.74, 39.79 and 49.17μM, respectively. |
| Animal experiment [2]: | |
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Animal models |
Male nude mice, Four-week-old |
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Preparation Method |
6.0×106 C4-2B-ENZR cells, or 3.0×106 22Rv1 cells were injected subcutaneously into the mice. After the mice were surgically castrated, they were randomized into four groups (n=5/group) and treated as follows: (1) vehicle control (PBS, i.p.); (2) MDV3100 (10mg/kg, p.o.); (3) KIF15-IN-1 (10mg/kg, i.p.); (4) MDV3100 (10mg/kg, p.o.) + KIF15-IN-1 (10mg/kg, i.p.). Tumor tissues were harvested and weighed after 4 weeks of treatment. Tumor size was measured twice a week. |
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Dosage form |
(1) vehicle control (PBS, i.p.); (2) MDV3100 (10mg/kg, p.o.); (3) KIF15-IN-1 (10mg/kg, i.p.); (4) MDV3100 (10mg/kg, p.o.) + KIF15-IN-1 (10mg/kg, i.p.)/p> |
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Applications |
C4-2B-ENZR and 22Rv1 tumors treated with MDV3100 alone showed no difference to the control groups (MDV3100 vs. control; C4-2B-ENZR, 1145±119.3 vs. 1269±182mm3; 22Rv1, 1455±127.5 vs. 1547±97.93mm3). However, KIF15-IN-1 treatment reduced the tumor volume (C4-2B-ENZR, 633.5±85.3mm3; 22Rv1, 905.4±124.5mm3), and the combination of MDV3100 and KIF15-IN-1 induced further inhibition in tumor growth (C4-2B-ENZR,246.3±67.42mm3; 22Rv1, 481.5±87.82mm3). |
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References: [1]. Li J, Wu H, et al. Enhanced antitumor efficacy by combining afatinib with MDV3100 in castration-resistant prostate cancer. Pharmazie. 2022;77(2):59-66. [2]. Gao L, Zhang W, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039. |
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MDV3100(enzalutamide) is a second-generation AR antagonist with an IC50 of 36nM in LNCaP prostate cells[1,2]. MDV3100 could reduce androgen binding to AR, inhibit AR transport to the nucleus and prevent the binding of AR to androgen response elements[2].
MDV3100 combined with TKIs exerted a synergistic effect on a variety of PCa cells. MDV3100 combined with afatinib could suppress the proliferation and migration of 22RV1 cells, as well as cause their cell cycle arrest and apoptosis[2]. MDV3100 probed the bone microenvironment that led to stronger cancer cell adaptive responses and osteomimicry than bicalutamide. MDV3100 presented with better treatment response, in line with MDV3100 delaying time to bone-related events and MDV3100 extending survival in mCRPC[3]. MDV3100 promoted macrophage migration to PCa cells that consequently led to enhanced PCa cell invasion in human (C4-2B/THP1) and mouse (TRAMP-C1/RAW264.7) PCa cells–macrophages co-culture systems[4]
MDV3100 combination with KIF15 inhibitors significantly suppressed MDV3100-resistant PCa cell growth and xenograft progression. KIF15 inhibitors may enhance the sensitivity of prostate tumors to MDV3100 treatment, and rationalize a combination therapy of KIF15 inhibitors with MDV3100 to treat CRPC patients [5]. The antitumor efficacy of MDV3100 can be substantially improved by methylselenol prodrug, which also downregulates AR-FL and AR-Vs in vivo[6]. MDV3100 prolonged overall survival of metastatic CRPC patients who progressed after chemotherapy in a Phase III trial[7]
References:
[1]. Tran C, Ouk S, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324(5928):787-790.
[2]. Li J, Wu H, et al. Enhanced antitumor efficacy by combining afatinib with MDV3100 in castration-resistant prostate cancer. Pharmazie. 2022;77(2):59-66.
[3]. Bock N, Kryza T, et al. In vitro engineering of a bone metastases model allows for study of the effects of antiandrogen therapies in advanced prostate cancer. Sci Adv. 2021;7(27):eabg2564.
[4]. Lin TH, Izumi K, et al. Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis. 2013;4(8):e764.
[5]. Gao L, Zhang W, et al. KIF15-Mediated Stabilization of AR and AR-V7 Contributes to Enzalutamide Resistance in Prostate Cancer. Cancer Res. 2021;81(4):1026-1039.
[6]. Zhan Y, Cao B, et al. Methylselenol prodrug enhances MDV3100 efficacy for treatment of castration-resistant prostate cancer. Int J Cancer. 2013;133(9):2225-2233.
[7]. Scher HI, Fizazi K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367(13):1187-1197.
MDV3100(enzalutamide) 是第二代 AR 拮抗剂,在 LNCaP 前列腺细胞中的 IC50 为 36nM[1,2]。 MDV3100可减少雄激素与AR的结合,抑制AR向细胞核的转运,阻止AR与雄激素反应元件的结合[2]。
MDV3100 联合 TKIs 对多种 PCa 细胞产生协同作用。 MDV3100联合阿法替尼可抑制22RV1细胞的增殖和迁移,并引起细胞周期停滞和凋亡[2]。 MDV3100 探测了导致比比卡鲁胺更强的癌细胞适应性反应和骨拟态的骨微环境。 MDV3100 表现出更好的治疗反应,与 MDV3100 延迟骨骼相关事件的时间和 MDV3100 延长 mCRPC 的生存期[3] 一致。 MDV3100 促进巨噬细胞向 PCa 细胞迁移,从而导致增强 PCa 细胞在人 (C4-2B/THP1) 和小鼠 (TRAMP-C1/RAW264.7) PCa 细胞-巨噬细胞共培养系统中的侵袭[4]
MDV3100 与 KIF15 抑制剂的组合显着抑制了 MDV3100 抗性 PCa 细胞生长和异种移植进展。 KIF15 抑制剂可增强前列腺肿瘤对 MDV3100 治疗的敏感性,并合理化 KIF15 抑制剂与 MDV3100 联合治疗 CRPC 患者[5]。甲基硒醇前体药物可显着提高 MDV3100 的抗肿瘤功效,甲基硒醇前体药物还可在体内下调 AR-FL 和 AR-Vs[6]。在一项 III 期试验中,MDV3100 延长了化疗后进展的转移性 CRPC 患者的总生存期[7]
| Cas No. | 915087-33-1 | SDF | |
| 别名 | 恩杂鲁胺; MDV3100 | ||
| 化学名 | 4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-fluoro-N-methylbenzamide | ||
| Canonical SMILES | CC1(C(=O)N(C(=S)N1C2=CC(=C(C=C2)C(=O)NC)F)C3=CC(=C(C=C3)C#N)C(F)(F)F)C | ||
| 分子式 | C21H16F4N4O2S | 分子量 | 464.4 |
| 溶解度 | ≥ 23.22mg/mL in DMSO | 储存条件 | Store at-20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1533 mL | 10.7666 mL | 21.5332 mL |
| 5 mM | 0.4307 mL | 2.1533 mL | 4.3066 mL |
| 10 mM | 0.2153 mL | 1.0767 mL | 2.1533 mL |
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ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer
Purpose: Enzalutamide, a potent androgen-receptor inhibitor, has demonstrated significant benefits in metastatic and nonmetastatic castration-resistant prostate cancer. We evaluated the efficacy and safety of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). Methods: ARCHES (ClinicalTrials.gov identifier: NCT02677896) is a multinational, double-blind, phase III trial, wherein 1,150 men with mHSPC were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus androgen deprivation therapy (ADT), stratified by disease volume and prior docetaxel chemotherapy. The primary end point was radiographic progression-free survival. Results: As of October 14, 2018, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT versus placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < .001; median not reached v 19.0 months). Similar significant improvements in radiographic progression-free survival were reported in prespecified subgroups on the basis of disease volume and prior docetaxel therapy. Enzalutamide plus ADT significantly reduced the risk of prostate-specific antigen progression, initiation of new antineoplastic therapy, first symptomatic skeletal event, castration resistance, and reduced risk of pain progression. More men achieved an undetectable prostate-specific antigen level and/or an objective response with enzalutamide plus ADT (P < .001). Patients in both treatment groups reported a high baseline level of quality of life, which was maintained over time. Grade 3 or greater adverse events were reported in 24.3% of patients who received enzalutamide plus ADT versus 25.6% of patients who received placebo plus ADT, with no unexpected adverse events. Conclusion: Enzalutamide with ADT significantly reduced the risk of metastatic progression or death over time versus placebo plus ADT in men with mHSPC, including those with low-volume disease and/or prior docetaxel, with a safety analysis that seems consistent with the safety profile of enzalutamide in previous clinical trials in castration-resistant prostate cancer.
Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer
Background: Men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising prostate-specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration-resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level.
Methods: In this double-blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration-resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen-deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis-free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression).
Results: A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis-free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (39.6 vs. 17.7 months; hazard ratio, 0.21; P<0.001; such therapy was used in 15% vs. 48% of patients) as was the time to PSA progression (37.2 vs. 3.9 months; hazard ratio, 0.07; P<0.001; progression occurred in 22% vs. 69% of patients). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo.
Conclusions: Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924 .).
Increased survival with enzalutamide in prostate cancer after chemotherapy
Background: Enzalutamide (formerly called MDV3100) targets multiple steps in the androgen-receptor-signaling pathway, the major driver of prostate-cancer growth. We aimed to evaluate whether enzalutamide prolongs survival in men with castration-resistant prostate cancer after chemotherapy.
Methods: In our phase 3, double-blind, placebo-controlled trial, we stratified 1199 men with castration-resistant prostate cancer after chemotherapy according to the Eastern Cooperative Oncology Group performance-status score and pain intensity. We randomly assigned them, in a 2:1 ratio, to receive oral enzalutamide at a dose of 160 mg per day (800 patients) or placebo (399 patients). The primary end point was overall survival.
Results: The study was stopped after a planned interim analysis at the time of 520 deaths. The median overall survival was 18.4 months (95% confidence interval [CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3 to 15.8) in the placebo group (hazard ratio for death in the enzalutamide group, 0.63; 95% CI, 0.53 to 0.75; P<0.001). The superiority of enzalutamide over placebo was shown with respect to all secondary end points: the proportion of patients with a reduction in the prostate-specific antigen (PSA) level by 50% or more (54% vs. 2%, P<0.001), the soft-tissue response rate (29% vs. 4%, P<0.001), the quality-of-life response rate (43% vs. 18%, P<0.001), the time to PSA progression (8.3 vs. 3.0 months; hazard ratio, 0.25; P<0.001), radiographic progression-free survival (8.3 vs. 2.9 months; hazard ratio, 0.40; P<0.001), and the time to the first skeletal-related event (16.7 vs. 13.3 months; hazard ratio, 0.69; P<0.001). Rates of fatigue, diarrhea, and hot flashes were higher in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.
Conclusions: Enzalutamide significantly prolonged the survival of men with metastatic castration-resistant prostate cancer after chemotherapy. (Funded by Medivation and Astellas Pharma Global Development; AFFIRM ClinicalTrials.gov number, NCT00974311.).
Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer
Background: The efficacy and safety of cabazitaxel, as compared with an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or enzalutamide) are unclear.
Methods: We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling-targeted inhibitor (abiraterone or enzalutamide) to receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling-targeted inhibitor (either 1000 mg of abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end point was imaging-based progression-free survival. Secondary end points of survival, response, and safety were assessed.
Results: A total of 255 patients underwent randomization. After a median follow-up of 9.2 months, imaging-based progression or death was reported in 95 of 129 patients (73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in the group that received an androgen-signaling-targeted inhibitor (hazard ratio, 0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imaging-based progression-free survival was 8.0 months with cabazitaxel and 3.7 months with the androgen-signaling-targeted inhibitor. The median overall survival was 13.6 months with cabazitaxel and 11.0 months with the androgen-signaling-targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P = 0.008). The median progression-free survival was 4.4 months with cabazitaxel and 2.7 months with an androgen-signaling-targeted inhibitor (hazard ratio for progression or death, 0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in 35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was noted in 36.5% and 11.5% (P = 0.004). Adverse events of grade 3 or higher occurred in 56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgen-signaling-targeted inhibitor. No new safety signals were observed.
Conclusions: Cabazitaxel significantly improved a number of clinical outcomes, as compared with the androgen-signaling-targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castration-resistant prostate cancer who had been previously treated with docetaxel and the alternative androgen-signaling-targeted agent (abiraterone or enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.).
Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design
PARP inhibitors in combination with androgen receptor-targeted therapy have demonstrated potential in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Here, we describe the design and rationale of the multinational, phase III, two-part TALAPRO-2 study comparing talazoparib plus enzalutamide versus placebo plus enzalutamide as a first-line treatment for patients with mCRPC with or without DNA damage response (DDR) alterations. This study has two co-primary end points: radiographic progression-free survival (rPFS) by blinded independent clinical review in all-comers (cohort 1) and in patients with DDR alterations (cohort 2). TALAPRO-2 will demonstrate whether talazoparib plus enzalutamide can significantly improve the efficacy of enzalutamide in terms of rPFS in both molecularly unselected and DDR-deficient patients with mCRPC (NCT03395197). Clinical Trial Registration: NCT03395197 (ClinicalTrials.gov).