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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.PIK3CA is one of the most frequently mutated oncogenes, with the resulting mutated p110α protein it encodes playing a central role in tumor cell proliferation. Chemotherapeutic agents targeting the PI3K p110α catalytic subunit have shown antitumor activity and a manageable safety profile - some of which are in clinical use, like [alpelisib] - but preclinical studies have shown that PI3K pathway inhibition releases negative feedback and activates receptor tyrosine kinase signaling, reengaging the pathway and attenuating drug activity. Newer PI3K inhibitors, like inavolisib, seek to mitigate this attenuation. Inavolisib is an inhibitor of PI3Kα that was approved by the FDA in October 2024 for the treatment of certain patients with advanced breast cancers. In February 2025, it was approved by Health Canada for the same indication.
Inavolisib is a Kinase Inhibitor. The mechanism of action of inavolisib is as a Phosphoinositide 3-Kinase alpha Inhibitor.
Physicochemical Properties
| Molecular Formula | C18H19F2N5O4 |
| Molecular Weight | 407.3714 |
| Exact Mass | 407.14 |
| Elemental Analysis | C, 53.07; H, 4.70; F, 9.33; N, 17.19; O, 15.71 |
| CAS # | 2060571-02-8 |
| Related CAS # | 2060571-02-8 |
| PubChem CID | 124173720 |
| Appearance | White to yellow solid powder |
| LogP | 1.5 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 8 |
| Rotatable Bond Count | 5 |
| Heavy Atom Count | 29 |
| Complexity | 641 |
| Defined Atom Stereocenter Count | 2 |
| SMILES | C[C@@H](C(=O)N)NC1=CC2=C(C=C1)C3=NC(=CN3CCO2)N4[C@@H](COC4=O)C(F)F |
| InChi Key | SGEUNORSOZVTOL-CABZTGNLSA-N |
| 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 |
| 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 |
| Synonyms | GDC-0077; RG-6114; GDC 0077; Inavolisib; 2060571-02-8; Itovebi; RG 6114; GDC0077; RG6114 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | PI3Kα (IC50 = 0.038 nM) |
| 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. |
| 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. |
| 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 - attained by approximately day 5 - the AUC and Cmax of inavolisib are 1010 h*ng/mL and 69 ng/mL, respectively. The time to maximum plasma concentration (Tmax) at steady-state is 3 hours. Route of Elimination Following oral administration of a single radiolabeled dose of inavolisib, 49% of the administered dose was recovered in the urine (40% as unchanged parent drug) and 48% was recovered in the feces (11% as unchanged parent drug). Volume of Distribution The apparent volume of distribution of inavolisib is 155 liters. Clearance The total clearance of inavolisib is 8.8 L/h. Protein Binding Inavolisib is 37% protein-bound in plasma. Metabolism / Metabolites Inavolisib is primarily metabolized via hydrolysis. _In vitro_, it appears minimally metabolized by CYP3A enzymes. Biological Half-Life The elimination half-life of inavolisib is 15 hours. |
| Toxicity/Toxicokinetics |
Hepatotoxicity
In the prelicensure trials of inavolisib in combination with palbociclib and fulvestrant as therapy of advanced or metastatic breast cancer, liver test abnormalities were frequent, with elevations in ALT levels in 34% compared to 29% of those on placebo with palbociclib and fulvestrant. The enzyme elevations were usually transient, mild-to-moderate in severity and not associated with symptoms or jaundice. ALT elevations above 5 times the upper limit of normal (ULN) arose in 3% vs 1.2% with placebo. Because inavolisib was always given in combination with other kinase inhibitors and hormonal agents, it was difficult to attribute the liver test abnormalities to inavolisib alone. There were no discontinuations of inavolisib because of liver test abnormalities and no episodes of clinically apparent liver injury or deaths from liver failure. Since approval and clinical availability of inavolisib, there have been no published case reports of clinically apparent liver injury with jaundice, but clinical experience with its use has been limited. Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury). |
| References |
[1]. Cancer Res (2018) 78 (4_Supplement): PD4-14. [2].Cancer Res (2018) 78 (4_Supplement): PD4-14. |
| Additional Infomation |
Inavolisib (GDC-0077) is under investigation in clinical trial NCT03006172 (To Evaluate the Safety, Tolerability, and Pharmacokinetics of GDC-0077 Single Agent in Participants With Solid Tumors and in Combination With Endocrine and Targeted Therapies in Participants With Breast Cancer). Inavolisib is an orally available inhibitor of phosphatidylinositol 3-kinase (PI3K), with potential antineoplastic activity. 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. |
Solubility Data
| Solubility (In Vitro) | DMSO: 81~110 mg/mL (198.8~270 mM) |
| 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. 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. 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |