GDC-0077 (RG6114)
(Synonyms: GDC-0077; RG6114) 目录号 : GC32710
Inavolisib (GDC-0077, RG6114, RO-7113755) is a potent selective inhibitor of PI3K alpha (PI3Kα) with an IC50 of 0.038 nM. GDC-0077 is >300-fold more selective for PI3K alpha over the other class I PI3K isoforms (beta, delta, and gamma) and >2000-fold more selective over PIK family members. GDC-0077 binds to the ATP binding site of PI3K and inhibits the phosphorylation of PIP2 to PIP3.
Cas No.:2060571-02-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Inavolisib (GDC-0077, RG6114, RO-7113755) is a potent selective inhibitor of PI3K alpha (PI3Kα) with an IC50 of 0.038 nM. GDC-0077 is >300-fold more selective for PI3K alpha over the other class I PI3K isoforms (beta, delta, and gamma) and >2000-fold more selective over PIK family members. GDC-0077 binds to the ATP binding site of PI3K and inhibits the phosphorylation of PIP2 to PIP3.
GDC-0077 potently inhibits mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation.[2]
GDC-0077 treatment at the MTD in vivo results in tumor regressions in multiple PIK3CA-mutant xenograft and patient-derived xenograft models.[2]
[1] R Hong, et al. Cancer Research, DOI: 10.1158/1538-7445.SABCS17-PD4-14 [2] Song KW, et al. Cancer Discov. 2022 Jan;12(1):204-219.
| Cas No. | 2060571-02-8 | SDF | |
| 别名 | GDC-0077; RG6114 | ||
| Canonical SMILES | C[C@@H](C(N)=O)NC1=CC=C(C2=NC(N3[C@H](C(F)F)COC3=O)=CN2CCO4)C4=C1 | ||
| 分子式 | C18H19F2N5O4 | 分子量 | 407.37 |
| 溶解度 | DMSO : ≥ 180 mg/mL (441.86 mM) | 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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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.4548 mL | 12.2739 mL | 24.5477 mL |
| 5 mM | 0.491 mL | 2.4548 mL | 4.9095 mL |
| 10 mM | 0.2455 mL | 1.2274 mL | 2.4548 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
RTK-Dependent Inducible Degradation of Mutant PI3Kα Drives GDC-0077 (Inavolisib) Efficacy
Cancer Discov 2022 Jan;12(1):204-219.PMID:34544753DOI:10.1158/2159-8290.CD-21-0072.
PIK3CA is one of the most frequently mutated oncogenes; the p110a protein it encodes plays a central role in tumor cell proliferation. Small-molecule inhibitors targeting the PI3K p110a catalytic subunit have entered clinical trials, with early-phase GDC-0077 studies showing antitumor activity and a manageable safety profile in patients with PIK3CA-mutant breast cancer. However, preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Here we discover that GDC-0077 and taselisib more potently inhibit mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation. Both are more effective than other PI3K inhibitors at maintaining prolonged pathway suppression. This study establishes a new strategy for identifying inhibitors that specifically target mutant tumors by selective degradation of the mutant oncoprotein and provide a strong rationale for pursuing PI3Kα degraders in patients with HER2-positive breast cancer. SIGNIFICANCE: The PI3K inhibitors GDC-0077 and taselisib have a unique mechanism of action; both inhibitors lead to degradation of mutant p110a protein. The inhibitors that have the ability to trigger specific degradation of mutant p110a without significant change in wild-type p110a protein may result in improved therapeutic index in PIK3CA-mutant tumors.See related commentary by Vanhaesebroeck et al., p. 20.This article is highlighted in the In This Issue feature, p. 1.
Discovery of GDC-0077 (Inavolisib), a Highly Selective Inhibitor and Degrader of Mutant PI3Kα
J Med Chem 2022 Dec 22;65(24):16589-16621.PMID:36455032DOI:10.1021/acs.jmedchem.2c01422.
Small molecule inhibitors that target the phosphatidylinositol 3-kinase (PI3K) signaling pathway have received significant interest for the treatment of cancers. The class I isoform PI3Kα is most commonly associated with solid tumors via gene amplification or activating mutations. However, inhibitors demonstrating both PI3K isoform and mutant specificity have remained elusive. Herein, we describe the optimization and characterization of a series of benzoxazepin-oxazolidinone ATP-competitive inhibitors of PI3Kα which also induce the selective degradation of the mutant p110α protein, the catalytic subunit of PI3Kα. Structure-based design informed isoform-specific interactions within the binding site, leading to potent inhibitors with greater than 300-fold selectivity over the other Class I PI3K isoforms. Further optimization of pharmacokinetic properties led to excellent in vivo exposure and efficacy and the identification of clinical candidate GDC-0077 (inavolisib, 32), which is now under evaluation in a Phase III clinical trial as a treatment for patients with PIK3CA-mutant breast cancer.
Effective Combination Therapies for the Treatment of HER2 Cancer
ACS Med Chem Lett 2023 Feb 7;14(3):231-232.PMID:PMC10009784DOI:10.1021/acsmedchemlett.2c00544.
Breast cancer (BC) is the primary cause of cancer-related death among women worldwide. The human epidermal growth factor receptor type 2 (HER2)-positive BC accounts for ∼15% of all BCs and a relatively poor prognosis. The disclosure in this patent highlight relates to a combination therapy comprising inavolisib (GDC-0077) and a HER2-targeted therapy such as trastuzumab, pertuzumab, or their combination for the treatment of HER2-overexpressing breast cancer.
PI3K inhibitors in trastuzumab-resistant HER2-positive breast cancer cells with PI3K pathway alterations
Am J Cancer Res 2022 Jul 15;12(7):3067-3082.PMID:35968355doi
The activation of the PI3K signaling pathway resulting from genetic alterations induces carcinogenesis and resistance to anticancer therapies. Breast cancer is a major malignancy that is associated with dysregulation of the PI3K signaling pathway. PIK3CA mutations and PTEN loss occur in every subtype of breast cancer. PI3K inhibitors are being evaluated in breast cancer after the success of an alpha isoform-specific PI3K inhibitor in estrogen receptor (ER)-positive/HER2-negative metastatic breast cancer. Some preclinical data indicate the potential for PI3K/mTOR targeting in combination with trastuzumab for HER2-positive breast cancer with or without expression of the estrogen receptor. However, the role of this therapy in HER2-positive breast cancer with PIK3CA mutations and/or PTEN loss remains unclear. We examined three HER2-positive, ER-negative breast cancer cell lines to determine the efficacy of a novel alpha isoform-specific PI3K inhibitor in combination with trastuzumab. The results indicated that this combination was effective in PIK3CA-mutant or PTEN-deficient breast cancer cells by inducing apoptosis and inhibiting the expression of downstream proteins. PTEN loss by siRNA modulation in parental HER2-positive cancer cells with PI3K signaling pathway alterations could not confer resistance to alpelisib or GDC-0077 plus trastuzumab. We selected the CK-MB-1 cell line without alterations in the PI3K pathway to demonstrate that PI3K inhibitors plus trastuzumab represented a biomarker-specific treatment. In vivo effects of alpelisib plus trastuzumab were tested and confirmed in a mouse model, showing the combination strategy offered the best opportunity to achieve tumor volume reduction. With known safety profiles, this cytotoxic chemotherapy-free regimen warrants further attention as a biomarker-driven strategy for treating HER2-positive breast cancer.