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Purity: ≥98%
Inavolisib (RG6114; GDC0077), extracted from patent WO 2017001645 A1, formula I, is a novel, potent and orally bioavailable PI3K inhibitor with potential anticancer activity. It acts by blocking PI3K which is overactive in cancer. Inhibition of PI3K prevents the activation of the PI3K-mediated signaling pathway and results in the inhibition of growth and survival of PI3K-overexpressing tumor cells.
On October 10, 2024, the Food and Drug Administration approved inavolisib (Itovebi, Genentech, Inc.) with palbociclib and fulvestrant for adults with endocrine-resistant, PIK3CA-mutated, hormone receptor (HR)-positive, human epidermal growth-factor receptor 2 (HER2)-negative, locally advanced or metastatic breast cancer, as detected by an FDA-approved test, following recurrence on or after completing adjuvant endocrine therapy.| Targets |
PI3Kα (IC50 = 0.038 nM)
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|---|---|
| ln Vitro |
GDC-0077 effectively inhibits mutant PI3K pathway signaling and cell viability through unique HER2-dependent mutant p110a degradation.[2]
Inavolisib is a mutant-selective PI3Kα inhibitor that targets the p110α catalytic subunit of PI3Kα, specifically in its mutated form. PI3Kα is a critical component of the PI3K pathway, which is activated by receptor tyrosine kinases (RTKs) at the plasma membrane. This pathway regulates cell growth, survival, and metabolism. In non-mutant settings, inhibition of PI3Kα by standard PI3K inhibitors leads to initial suppression of the pathway. However, feedback mechanisms often upregulate RTK expression, leading to sustained PI3K signaling despite the inhibition. In contrast, inavolisib selectively binds to the mutant p110α/p85β complex, triggering proteasome-mediated degradation of the mutant p110α subunit. This degradation disrupts downstream signaling and prevents feedback reactivation of the PI3K pathway. By degrading mutant p110α, inavolisib achieves sustained inhibition of PI3K signaling, particularly in tumors driven by activating mutations in PI3Kα. |
| ln Vivo |
GDC-0077 treatment at the MTD in vivo results in tumor regressions in multiple PIK3CA-mutant xenograft and patient-derived xenograft models.[2]
Pharmacodynamics: The exposure-response relationship in regards to inavolisib efficacy has not been characterized. Higher systemic exposure of inavolisib was associated with higher incidence of Grade ≥2 anemia, Grade ≥2 hyperglycemia, and inavolisib dosage modifications due to adverse reactions. Inavolisib is a small molecule inhibitor of phosphatidylinositol 3-kinase and is used in combination with other antineoplastic agents to treat selected adults with locally advanced or metastatic breast cancer. Inavolisib is associated with transient elevations in serum aminotransferase levels during therapy but has not been linked to episodes of clinically apparent liver injury with jaundice. Inavolisib is an orally available inhibitor of phosphatidylinositol 3-kinase (PI3K), with potential antineoplastic activity. Upon administration, inavolisib binds to and inhibits various members of the PI3K family, including activating mutations in the catalytic alpha isoform PIK3CA. PI3K inhibition prevents the activation of the PI3K-mediated signaling pathway and results in the inhibition of growth and survival of PI3K-overexpressing tumor cells. Dysregulation of the PI3K signaling pathway is frequently associated with tumorigenesis and tumor resistance to a variety of antineoplastic agents and radiotherapy. PIK3CA, which encodes the p110-alpha catalytic subunit of the class I PI3K, is frequently mutated in a variety of cancer cell types and plays a key role in cancer cell growth and invasion. INAVOLISIB is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2024 and is indicated for breast cancer and has 3 investigational indications. |
| Enzyme Assay |
Dorsomorphin dihydrochloride (BML-275 dihydrochloride; Compound C dihydrochloride) is a potent, selective and ATP-competitiveAMPKinhibitor, with aKiof 109 nM. Dorsomorphin dihydrochloride inhibits BMP pathway by targeting the type I receptorsALK2,ALK3, andALK6.
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| Cell Assay |
ATP-based cell viability assay in Colon cancer cell lines. Colon cancer cell lines treated with GDC-0077 at gradient concentrations for 24 hours underwent a Western blot to measure the levels of the protein p110a and pAKT signaling.
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| Animal Protocol |
Female NCR nude mice inoculated with HCC1954 tumor cells, female NOD-SCID gamma mice inoculated with WHIM20 tumor cells, female NOD-SCID gamma mice inoculated with HCI-003 tumor cells
25 mg/kg Oral gavage |
| ADME/Pharmacokinetics |
Absorption
The absolute oral bioavailability of inavolisib is 76%. At steady state (reached approximately day 5), the AUC and Cmax of inavolisib are 10¹⁰ hng/mL and 69 ng/mL, respectively. The time to reach maximum plasma concentration (Tmax) at steady state is 3 hours. Elimination Route Following a single oral dose of radiolabeled inavolisib, 49% of the administered dose is recovered in the urine (40% of which is the original drug) and 48% is recovered in the feces (11% of which is the original drug). Volume of Distribution The apparent volume of distribution of inavolisib is 155 L. Clearance The total clearance of inavolisib is 8.8 L/h. Protein Binding The protein binding rate of inavolisib in plasma is 37%. Metabolites/Metabolites Inavalib is primarily metabolized via hydrolysis. In vitro studies have shown that it is hardly metabolized by the CYP3A enzyme. Biological Half-Life The elimination half-life of inavalib is 15 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In premarketing trials of inavolisib in combination with palbociclib and fulvestrant for the treatment of advanced or metastatic breast cancer, liver dysfunction was common, with elevated alanine aminotransferase (ALT) levels in 34% of patients compared to 29% in the placebo group (palbociclib plus fulvestrant). These enzyme elevations were usually transient, mild to moderate in severity, and without symptoms or jaundice. ALT levels exceeding 5 times the upper limit of normal (ULN) were observed in 3% of patients, compared to 1.2% in the placebo group. Because inavolisib is consistently used in combination with other kinase inhibitors and hormonal drugs, it is difficult to attribute liver dysfunction to inavolisib itself. There were no cases of discontinuation of inavolisib due to liver dysfunction, nor were there any clinically significant cases of liver injury or death due to liver failure. Since the approval of inavilisib, there have been no published case reports of clinically presenting liver injury with jaundice, but clinical experience with its use is limited. Probability Score: E (Unproven but suspected rare cause of clinically presenting liver injury). |
| References | |
| Additional Infomation |
Inavolisib (GDC-0077) is currently undergoing clinical trial NCT03006172 (evaluating the safety, tolerability, and pharmacokinetics of GDC-0077 as monotherapy in patients with solid tumors and in combination with endocrine and targeted therapies in patients with breast cancer). Inavolisib is an oral phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antitumor activity. Inavolisib binds to and inhibits multiple members of the PI3K family, including activating mutations in the catalytic subtype PIK3CA. PI3K inhibition prevents the activation of PI3K-mediated signaling pathways, thereby inhibiting the growth and survival of PI3K-overexpressing tumor cells. PI3K signaling pathway dysregulation is frequently associated with tumorigenesis and tumor resistance to multiple antitumor drugs and radiotherapy. PIK3CA encodes the p110-α catalytic subunit of class I PI3K, is frequently mutated in various cancer cell types, and plays a crucial role in cancer cell growth and invasion.
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| Molecular Formula |
C18H19F2N5O4
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|---|---|
| Molecular Weight |
407.3714
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| Exact Mass |
407.14
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| Elemental Analysis |
C, 53.07; H, 4.70; F, 9.33; N, 17.19; O, 15.71
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| CAS # |
2060571-02-8
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| Related CAS # |
2060571-02-8
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| PubChem CID |
124173720
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| Appearance |
White to yellow solid powder
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| LogP |
1.5
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
641
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@@H](C(=O)N)NC1=CC2=C(C=C1)C3=NC(=CN3CCO2)N4[C@@H](COC4=O)C(F)F
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| InChi Key |
SGEUNORSOZVTOL-CABZTGNLSA-N
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| InChi Code |
InChI=1S/C18H19F2N5O4/c1-9(16(21)26)22-10-2-3-11-13(6-10)28-5-4-24-7-14(23-17(11)24)25-12(15(19)20)8-29-18(25)27/h2-3,6-7,9,12,15,22H,4-5,8H2,1H3,(H2,21,26)/t9-,12-/m0/s1
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| Chemical Name |
(2S)-2-[[2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]amino]propanamide
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| Synonyms |
GDC-0077; RG-6114; GDC 0077;
Inavolisib; 2060571-02-8; Itovebi; RG 6114; GDC0077; RG6114
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 81~110 mg/mL (198.8~270 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.75 mg/mL (6.75 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.75 mg/mL (6.75 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.08 mg/mL (5.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 5: ≥ 0.55 mg/mL (1.35 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4548 mL | 12.2739 mL | 24.5477 mL | |
| 5 mM | 0.4910 mL | 2.4548 mL | 4.9095 mL | |
| 10 mM | 0.2455 mL | 1.2274 mL | 2.4548 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT04632992 | Active Recruiting |
Drug: Inavolisib Drug: Alectinib |
Advanced Unresectable | Genentech, Inc. | January 13, 2021 | Phase 2 |
| NCT05646862 | Recruiting | Drug: Inavolisib Drug: Alpelisib |
Breast Cancer | Hoffmann-La Roche | June 7, 2023 | Phase 3 |
| NCT04191499 | Recruiting | Drug: Inavolisib Drug: Placebo |
Breast Cancer | Hoffmann-La Roche | January 29, 2020 | Phase 2 Phase 3 |
| NCT03006172 | Recruiting | Drug: Inavolisib Drug: Fulvestrant |
Breast Cancer Solid Tumor |
Genentech, Inc. | December 13, 2016 | Phase 1 |
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