2. MAPK/ERK Pathway Stem Cell/Wnt Protein Tyrosine Kinase/RTK
  3. ERK RET
  4. APS03118

APS03118 是一种口服有效、强效且高选择性的转染重排 (RET) 抑制剂。APS03118 广谱抑制 RET 融合及多种突变 (包括 G810、V804、L730 和 Y806 变体)，IC50 值普遍低于 1 nM (对野生型的 IC50 为 0.0952 nM；对突变体的 IC50 范围为 0.00438 至 5.72 nM)，并出对 RET G810 突变展现出显著的抑制活性。APS03118 能有效抑制整个 RET 信号通路 (包括 RET、Shc 和 ERK1/2)，并对大多数脱靶激酶具有超过 20 倍的选择性 (FLT3 和 YES 除外)。在体内模型中，APS03118 可在 KIF5B-RET 和 CCDC6-RET V804M PDX 小鼠模型中诱导肿瘤完全消退，并显著延长颅内 CCDC6-RET 转移小鼠模型中的生存期。APS03118 可用于针对选择性 RET 抑制剂 (SRI) 耐药的 RET 驱动型癌症的相关研究。

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APS03118

APS03118 Chemical Structure

CAS No. : 2598870-24-5

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APS03118 相关抗体

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  • 生物活性

  • 纯度 & 产品资料

  • 参考文献

生物活性

APS03118 is an orally active, potent and selective rearranged during transfection (RET) inhibitor. APS03118 broadly inhibits RET fusions and mutations (including G810, V804, L730, and Y806 variants), with IC50 values predominantly below 1 nM (0.095 nM for WT; ranging from 0.00438 to 5.72 nM for mutants), and demonstrates marked superiority against RET G810 mutations. APS03118 inhibits the entire RET signaling pathway (including RET, Shc, and ERK1/2), with >20-fold selectivity over most off-target kinases (except FLT3 and YES). APS03118 induces complete tumor regression in KIF5B-RET and CCDC6-RET V804 M patient derived xenografts (PDXs) and significantly prolongs survival in an intracranial CCDC6-RET metastasis mice model. APS03118 can be used for selective RET inhibitor (SRI)-resistant, RET-driven cancer research[1].

体外研究
(In Vitro)

APS03118 (compound 5) 对 RET 溶剂前沿 G810 突变的抑制活性显著优于 Selpercatinib (HY-114370) 和 Pralsetinib (HY-112301)[1]。
APS03118 对 ERT 耐药突变 (如溶剂前沿和守门员突变) 展示出卓越疗效，并且在天然 RET 融合阳性 LC2/ad 肺癌细胞中表现出与 Pralsetinib 和 Selpercatinib 相当的强效抗增殖活性 (IC50 = 10.08 nM)[1]。
APS03118 (0-3000 nM) 可强效抑制 Ba/F3 KIF5B-RET、Ba/F3 KIF5B-RET V804M、Ba/F3 KIF5B-RET G810R 和 Ba/F3 KIF5B-RET M918T 细胞中的 RET 自身磷酸化，IC50 值分别为 1.91、1.18、14.66 和 2.28 nM[1]。
APS03118 (0-1000 nM，1.5 小时) 在低纳摩尔浓度下即可有效抑制 TT-RET C634W 细胞中的整个 RET 信号通路 (包括 RET、Shc 和 ERK1/2)[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

APS03118 相关抗体:

Western Blot Analysis[1]

Cell Line: TT-RET C634W cells
Concentration: 0, 1, 10, 100, and 1000 nM
Incubation Time: 1.5 h
Result: Almost abolished the phosphorylation of RET, Shc and ERK1/2 at 10 nM, whereas Selpercatinib and Pralsetinib only partially inhibited it.
Inhibited the phosphorylation of RET, Shc, and ERK1/2 at concentrations below 10 nM.
体内研究
(In Vivo)

APS03118 (3、10 和 30 mg/kg，口服，每日两次，连续 28 天) 在 KIF5B-RET 和 CCDC6-RET V804M PDX 小鼠模型中均展现出强效的抗肿瘤作用[1]。
APS03118 (10 和 30 mg/kg，口服，每日两次，连续 90 天) 在颅内 CCDC6-RET 转移小鼠模型中可清除颅内肿瘤并延长生存期[1]。
APS03118 (10 和 30 mg/kg，口服，每日两次，连续 14 或 15 天) 在 Ba/F3 KIF5B-RET G810R 和 Ba/F3 KIF5B-RET V804M CDX 小鼠模型中可抑制肿瘤生长[1]。

MCE has not independently confirmed the accuracy of these methods. They are for reference only.

Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with KIF5B-RET tumors[1]
Dosage: 3, 10 and 30 mg/kg
Administration: p.o., BID for 28 days
Result: Inhibited tumor growth in a dose-dependent manner, with TGI of 85, 107, and 109 % at 3, 10, and 30 mg/kg, respectively.
Significantly reduced tumor volumes on day 17 compared to the vehicle.
Achieved complete tumor regression at 10 and 30 mg/kg at the study end point, matching the efficacy of Selpercatinib at its 10 mg/kg dose.
Revealed no significant body weight changes.
Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously implanted with CCDC6-RET V804M tumors[1]
Dosage: 3, 10 and 30 mg/kg
Administration: p.o., BID for 28 days
Result: Achieved tumor growth inhibition of 88, 99, and 100 %, at 3, 10, and 30 mg/kg, respectively.
Reduced tumor volumes in all tested group.
Reduced tumor size at 3 and 10 mg/kg, with efficacy comparable to Selpercatinib at its 10 mg/kg dose.
Revealed no significant body weight changes.
Animal Model: Female BALB/c nude mice (6-8 weeks) intracranially implanted with CCDC6-RET tumors into the brain[1]
Dosage: 10 and 30 mg/kg
Administration: p.o., BID for 90 days
Result: Significantly prolonged the survival time and demonstrated a 100 % survival rate at a dose of 10 mg/kg.
Induced complete regression of brain tumors at 10 and 30 mg/kg.
Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET G810R cells[1]
Dosage: 10 and 30 mg/kg
Administration: p.o., BID for 15 days
Result: Induced potent tumor growth inhibition with a TGI of 90 % at 30 mg/kg, while Selpercatinib achieved only 48 % TGI at the same dose.
Exhibited greater efficacy than Selpercatinib in slowing the growth of Ba/F3 KIF5B-RET G810R allograft tumors at the same dose.
Exhibited excellent tolerability at 10 and 30 mg/kg, with no significant body weight loss or apparent abnormalities in mice.
Significantly reduced tumor volume compared to control on day 11.
Animal Model: Female BALB/c nude mice (6-8 weeks) subcutaneously injected with Ba/F3 KIF5B-RET V804M cells[1]
Dosage: 10 mg/kg
Administration: p.o., BID for 14 days
Result: Achieved considerably higher TGI rates of 61 % compared to Selpercatinib (10 mg/kg, p.o., BID; TGI = 48 %).
Was well-tolerated with no significant body weight loss in mice compared to the vehicle group during the treatment period.
分子量

496.56

Formula

C27H28N8O2
CAS 号
运输条件

Room temperature in continental US; may vary elsewhere.
储存方式

Please store the product under the recommended conditions in the Certificate of Analysis.
纯度 & 产品资料
参考文献

APS03118 相关分类

  • 摩尔计算器

  • 稀释计算器

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  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

APS031182598870-24-5APS 03118APS-03118ERKRETExtracellular signal regulated kinasesRET-G810RET-V804RET-L730RET-Y806ShcERK1/2LC2/ad cellTT-RET C634W cellsKIF5B-RET PDXCCDC6-RET V804 M PDXintracranial CCDC6-RET metastasis modelSRI-resistant RET-driven cancerInhibitorinhibitorinhibit

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