更新于：2024-09-20
Tunlametinib
妥拉美替尼
更新于：2024-09-20
概要
基本信息
药物类型 小分子化药 |
别名 HL 085、HL-085、HL085 + [1] |
作用机制 MEK1抑制剂(双特异性丝裂原活化蛋白激酶激酶1抑制剂)、MEK2抑制剂(双特异性丝裂原活化蛋白激酶激酶2抑制剂) |
非在研适应症 |
原研机构  上海科州药物股份有限公司初创企业 |
在研机构 上海科州药物股份有限公司初创企业 |
非在研机构- |
最高研发阶段批准上市 |
首次获批日期 中国 (2024-03-12), |
最高研发阶段(中国)批准上市 |
特殊审评优先审评 (中国)、附条件批准 (中国) |
登录后查看首次获批时间轴
结构
分子式C16H12F2IN3O3S |
InChIKeyUFZJUVFSSINETF-UHFFFAOYSA-N |
CAS号1801756-06-8 |
关联
24
项与 妥拉美替尼 相关的临床试验一项评估HL-085胶囊联合维莫非尼治疗BRAF V600E突变不可切除局部晚期或转移性非小细胞肺癌（NSCLC）患者有效性和安全性的单臂、开放性、多中心 Ⅱ 期临床研究
A Multicenter, Randomized, Open-label, Phase 3 Study to Evaluate the Efficacy and Safety of Tunlametinib Plus Vemurafenib in Patients With BRAF V600E-mutant Metastatic Colorectal Cancer
Efficacy and Safety of Tunlametinib Capsules Versus Combination Chemotherapy of Investigator's Choice in Advanced NRAS-mutant Melanoma Patients Who Had Previously Received Immunotherapy
100 项与 妥拉美替尼 相关的临床结果
登录后查看更多信息
100 项与 妥拉美替尼 相关的转化医学
登录后查看更多信息
100 项与 妥拉美替尼 相关的专利（医药）
登录后查看更多信息
3
项与 妥拉美替尼 相关的文献（医药）2023-01-01Frontiers in pharmacology
Preclinical characterization of tunlametinib, a novel, potent, and selective MEK inhibitor.
Article
作者: Wang, Xingkai ; Huang, Gongchao ; Xia, Xiangying ; Cheng, Ying ; Tian, Hongqi ; Liu, Yahong
Background: Aberrant activation of RAS-RAF-MEK-ERK signaling pathway has been implicated in more than one-third of all malignancies. MEK inhibitors are promising therapeutic approaches to target this signaling pathway. Though four MEK inhibitors have been approved by FDA, these compounds possess either limited efficacy or unfavorable PK profiles with toxicity issues, hindering their broadly application in clinic. Our efforts were focused on the design and development of a novel MEK inhibitor, which subsequently led to the discovery of tunlametinib. Methods: This study verified the superiority of tunlametinib over the current MEK inhibitors in preclinical studies. The protein kinase selectivity activity of tunlametinib was evaluated against 77 kinases. Anti-proliferation activity was analyzed using the 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) or (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay. ERK and phospho-ERK levels were evaluated by Western blot analysis. Flow cytometry analysis was employed to investigate cell cycle and arrest. Cell-derived xenograft (CDX) and Patient-derived xenograft (PDX) models were used to evaluate the tumor growth inhibition. The efficacy of tunlametinib as monotherapy treatment was evaluated in KRAS/BRAF mutant or wild type xenograft model. Furthermore, the combination studies of tunlametinib with BRAF/KRASG12C/SHP2 inhibitors or chemotherapeutic agent were conducted by using the cell proliferation assay in vitro and xenograft models in vivo. Results: In vitro, tunlametinib demonstrated high selectivity with approximately 19-fold greater potency against MEK kinase than MEK162, and nearly 10-100-fold greater potency against RAS/RAF mutant cell lines than AZD6244. In vivo, tunlametinib resulted in dramatic tumor suppression and profound inhibition of ERK phosphorylation in tumor tissue. Mechanistic study revealed that tunlametinib induced cell cycle arrest at G0/G1 phase and apoptosis of cells in a dose-proportional manner. In addition, tunlametinib demonstrated a favorable pharmacokinetic profile with dose-proportionality and good oral bioavailability, with minimal drug exposure accumulation. Furthermore, tunlametinib combined with BRAF/KRASG12C/SHP2 inhibitors or docetaxel showed synergistically enhanced response and marked tumor inhibition. Conclusion: Tunlametinib exhibited a promising approach for treating RAS/RAF mutant cancers alone or as combination therapies, supporting the evaluation in clinical trials. Currently, the first-in-human phase 1 study and pivotal clinical trial of tunlametinib as monotherapy have been completed and pivotal trials as combination therapy are ongoing.
BMC medicine
First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations
Article
作者: Chen, Ling ; Jia, Zhongwei ; Zhao, Qian ; Fan, Li ; Hu, Pei ; Ji, Dongmei ; Guo, Jun ; Sun, Peng ; Luo, Zhiguo ; Wang, Xuan ; Si, Lu ; Chen, Jing ; Chen, Yu
Background:
HL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations.
Methods:
This was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5–18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D.
Results:
Between September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months.
Conclusions:
The HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.
Trial registration:
Trial registration ClinicalTrials.gov number: NCT03973151.
Frontiers in pharmacology
Phase I pharmacokinetic study of an oral, small-molecule MEK inhibitor tunlametinib in patients with advanced NRAS mutant melanoma
Article
作者: Wang, Huanhuan ; Fu, Diyi ; Cui, Cheng ; Cheng, Ying ; Hu, Pei ; Si, Lu ; Guo, Jun ; Wang, Teng ; Zhao, Qian ; Tian, Hongqi ; Zhong, Wen ; Xi, Wanlin
Background: Malignant melanoma is an aggressive disease. Tunlametinib (HL-085) is a potent, selective, and orally bioavailable MEK1/2 inhibitor. The objective of this study was to determine the pharmacokinetics (PK) of tunlametinib and its main metabolite M8 in patients with NRAS-mutant melanoma following a single dose and multiple doses in a phase I safety and PK study.Methods: A multiple-center phase I study was performed in patients with melanoma including dose-escalation phase and dose-expansion phase. PK following a single oral dose and multiple doses of 0.5–18 mg twice daily was assessed.Results: A total of 30 participants were included in the dose escalation phase and then 11 patients were included in the dose-expansion phase (12 mg twice daily). Tunlametinib plasma concentration rapidly increased after dosing, with a Tmax of 0.5–1 h. Mean elimination half-life (t1/2) was dose-independent and had a range from 21.84 to 34.41 h. Mean apparent clearance (CL/F) and distribution volume (V/F) were 28.44–51.93 L/h and 1199.36–2009.26 L, respectively. The average accumulation ratios of AUC and Cmax after the multiple administration of tunlametinib were 1.64–2.73 and 0.82–2.49, respectively. Tunlametinib was rapidly transformed into the main metabolite M8 and M8 reached the peak concentration about 1 h after administration. Mean t1/2 of M8 was 6.1–33.54 h. The body exposure of M8 in plasma was 36%–67% of that of tunlametinib. There were general dose-proportional increases in maximum concentration (Cmax) and area under the curve (AUC) of tunlametinib and M8 both in the single dose phase and in the multiple doses phase.Conclusion: Tunlametinib was absorbed rapidly and eliminated at a medium speed after drug withdrawal. Pharmacokinetic body exposure increased in general dose-proportional manner from 0.5 mg up to 18 mg. Slight accumulation was found after multiple oral doses. The pharmacokinetics of tunlametinib and its metabolite suggest that twice daily dosing is appropriate for tunlametinib.
100 项与 妥拉美替尼 相关的药物交易
登录后查看更多信息
研发状态
批准上市
10 条最早获批的记录, 后查看更多信息
登录
| 适应症 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|
| NRAS突变黑色素瘤 | 中国 |  上海科州药物股份有限公司初创企业 | 2024-03-12 |
未上市
10 条进展最快的记录, 后查看更多信息
登录
| 适应症 | 最高研发状态 | 国家/地区 | 公司 | 日期 |
|---|---|---|---|---|
| BRAF V600E突变结直肠癌 | 临床3期 | 中国 | 上海科州药物股份有限公司初创企业 | 2023-10-16 |
| BRAF V600E突变非小细胞肺癌 | 临床2期 | - | 上海科州药物股份有限公司初创企业 | 2023-09-24 |
| 转移性结直肠癌 | 临床2期 | 中国 | 上海科州药物股份有限公司初创企业 | 2022-02-24 |
| NF1突变型丛状神经纤维瘤 | 临床2期 | 中国 | 上海科州药物股份有限公司初创企业 | 2021-11-01 |
| 神经纤维瘤病1型 | 临床2期 | 中国 | 上海科州药物股份有限公司初创企业 | 2021-10-18 |
| 丛状神经纤维瘤 | 临床2期 | 中国 | 上海科州药物股份有限公司初创企业 | 2021-10-18 |
| BRAF突变阳性黑色素瘤 | 临床2期 | 中国 | 上海科州药物股份有限公司初创企业 | 2021-09-23 |
| 黑色素瘤 | 临床2期 | 中国 | 上海科州药物股份有限公司初创企业 | 2021-09-06 |
| RAS/RAF 突变的实体瘤 | 临床1期 | 中国 | 上海科州药物股份有限公司初创企业 | 2020-08-17 |
| KRAS突变非小细胞肺癌 | 临床1期 | 中国 | 上海科州药物股份有限公司初创企业 | 2020-05-21 |
登录后查看更多信息
临床结果
临床结果
适应症
分期
评价
查看全部结果
临床1期 | BRAF突变实体瘤 BRAF V600 | 72 | (NSCLC) | 網廠製壓網壓觸簾糧遞(糧壓繭廠鹽淵積膚製醖) = All 72 patients had treatment-related adverse events (TRAEs) 夢獵鏇鏇鑰淵製繭遞觸 (繭鑰鏇糧築簾艱齋糧窪 ) 更多 | 积极 | 2024-06-12 | |
(RP2D) | |||||||
临床2期 | 100 | 齋顧齋構糧淵窪獵餘淵(齋顧鹽艱夢窪鏇鑰齋醖) = 窪鏇鹹網襯憲網窪醖顧 鑰窪醖齋構積鹽鬱壓製 (壓製網糧鏇鹹艱鬱淵衊, 26.3% ~ 46.3%) 更多 | 积极 | 2024-05-24 | |||
临床2期 | BRAF V600 突变阳性黑色素瘤 BRAF V600E-mutant | 17 | 構蓋餘艱鹽壓願遞齋製(淵觸鏇窪廠構築襯選網) = 積鑰製鑰獵構壓糧膚鑰 遞壓簾窪繭鬱鏇憲齋餘 (觸鬱壓鑰醖鬱積廠蓋製, 44.0% ~ 89.7) 更多 | 积极 | 2024-05-24 | ||
临床1期 | 晚期恶性实体瘤 BRAF V600 mutation | 72 | 構廠廠壓鹹鏇繭願醖餘(繭鑰壓製觸廠鬱壓淵窪) = The most common AE were CK elevation, anemia and rash which were predominantly grade 1/2. 鏇艱廠製顧窪餘獵糧觸 (壓艱廠壓餘糧觸網餘積 ) | 积极 | 2023-10-23 | ||
(NSCLC) | |||||||
临床2期 | NRAS突变黑色素瘤 NRAS Mutation | 100 | 製窪範膚夢觸廠憲範餘(夢鏇餘衊醖醖鬱艱鹹襯) = 淵衊鹽鏇繭範獵餘糧範 襯繭鏇憲淵淵淵窪願夢 (觸鹹積繭網繭積衊繭鬱, 25.3 ~ 45.2) 更多 | 积极 | 2023-05-26 | ||
临床1期 | 42 | 淵遞憲簾簾觸繭膚鹹艱(鹹鹹餘鏇觸齋窪襯築鹽) = 膚願餘鏇簾網膚積積襯 鹹糧範繭夢齋顧衊鹽積 (艱網遞糧糧壓衊積餘淵 ) 更多 | - | 2023-01-04 | |||
临床1/2期 | 33 | 鹽鬱鏇顧選醖鬱遞鑰製(觸鏇淵簾觸襯醖願鏇壓) = the most common drug-related AEs were aspartate aminotransferase 餘糧襯壓選齋餘糧憲觸 (夢膚膚簾網鏇顧糧蓋醖 ) 更多 | 积极 | 2020-05-25 |
登录后查看更多信息
转化医学
使用我们的转化医学数据加速您的研究。
登录
或
药物交易
使用我们的药物交易数据加速您的研究。
登录
或
核心专利
使用我们的核心专利数据促进您的研究。
登录
或
临床分析
紧跟全球注册中心的最新临床试验。
登录
或
批准
利用最新的监管批准信息加速您的研究。
登录
或
特殊审评
只需点击几下即可了解关键药物信息。
登录
或
来和芽仔聊天吧
立即开始免费试用!
智慧芽新药情报库是智慧芽专为生命科学人士构建的基于AI的创新药情报平台，助您全方位提升您的研发与决策效率。
立即开始数据试用!
智慧芽新药库数据也通过智慧芽数据服务平台，以API或者数据包形式对外开放，助您更加充分利用智慧芽新药情报信息。
生物序列数据库
生物药研发创新
免费使用
化学结构数据库
小分子化药研发创新
免费使用