GDC-0077: Selective PI3Kα Inhibitor for Cancer Research

GDC-0077 is a highly selective, small-molecule inhibitor of phosphatidylinositol 3-kinase alpha (PI3Kα) that has emerged as a valuable research tool for dissecting the PI3K/AKT/mTOR signaling axis in cancer biology.

Also Known As

Inavolisib; RG6114

Primary Target

PI3Kα (PIK3CA gene product)

Selectivity

Highly selective for PI3Kα over PI3Kβ, PI3Kγ, and PI3Kδ isoforms

Molecular Formula

C23H26FN7O3S

Research Application

In vitro and in vivo oncology studies targeting PI3K/AKT/mTOR pathway

CAS Number

To be verified

Catalog SKU

G419993 (Aladdin Scientific)

Mechanism of Action

GDC-0077 (inavolisib) is a potent and selective inhibitor of the class I phosphoinositide 3-kinase alpha (PI3Kα) isoform, which is encoded by the PIK3CA gene. PI3Kα plays a central role in transducing growth factor receptor signals into intracellular responses that regulate cell survival, proliferation, and metabolism.

Upon binding to the ATP-binding pocket of PI3Kα, GDC-0077 competitively inhibits the enzyme's catalytic activity, thereby preventing the phosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5-trisphosphate (PIP3). This reduction in PIP3 levels attenuates the recruitment and activation of AKT at the plasma membrane, leading to downstream suppression of mTORC1 signaling and inhibition of tumor cell growth.

A notable feature of GDC-0077 is its reported ability to promote the degradation of mutant PI3Kα protein in addition to enzymatic inhibition, which may contribute to more durable pathway suppression compared with earlier-generation PI3K inhibitors. This dual activity has been highlighted as a potential advantage in PIK3CA-mutant cancer models.

Selectivity Profile and Biochemical Properties

One of the defining characteristics of GDC-0077 is its high isoform selectivity for PI3Kα relative to other class I PI3K family members (PI3Kβ, PI3Kγ, and PI3Kδ). This selectivity profile is important for research applications where investigators aim to delineate the specific contributions of PI3Kα to cellular signaling without confounding effects arising from pan-PI3K inhibition.

The compound's selectivity is attributed to interactions within the ATP-binding site that exploit structural differences between PI3Kα and other isoforms. As a result, GDC-0077 serves as a pharmacological tool to validate PI3Kα as a therapeutic target and to study isoform-specific biology in cell-based and animal model systems.

Key physicochemical parameters of GDC-0077 include its molecular formula C₂₃H₂₆FN₇O₃S and a molecular weight consistent with favorable drug-like properties. The compound is typically formulated in DMSO for in vitro studies. Researchers should prepare stock solutions according to established solubility guidelines and verify concentration by absorbance or mass spectrometry prior to biological assays.

Research Applications in Oncology

GDC-0077 is primarily used as a research tool compound in oncology programs focused on the PI3K/AKT/mTOR signaling pathway. PIK3CA is among the most frequently mutated oncogenes across human cancers, with high mutation rates reported in breast cancer, colorectal cancer, endometrial cancer, and other solid tumors. GDC-0077 enables researchers to model the pharmacological consequences of selective PI3Kα inhibition in these disease contexts.

In preclinical studies, GDC-0077 has been evaluated in cell viability assays, western blot analyses of AKT and S6K phosphorylation, apoptosis assays, and xenograft tumor models harboring PIK3CA mutations. The compound provides a mechanistic control for distinguishing PI3Kα-dependent from PI3Kα-independent cellular responses.

Clinically, GDC-0077 (inavolisib) has entered human trials, particularly in combination with endocrine therapy and CDK4/6 inhibitors for hormone receptor-positive, HER2-negative, PIK3CA-mutant breast cancer. Researchers designing translational studies may use GDC-0077 to establish in vitro pharmacodynamic benchmarks that mirror clinical dosing rationale. Its availability as a research reagent allows academic and industrial laboratories to replicate and extend findings from clinical-stage programs.

Handling, Storage, and Formulation Guidelines

Proper handling and storage of GDC-0077 are essential to maintain compound integrity and ensure reproducible experimental results. The compound should be stored as a lyophilized solid at −20 °C or below, protected from light and moisture. Upon receipt, researchers are advised to briefly centrifuge the vial before opening to consolidate any powder that may have adhered to the cap or walls during shipping.

For stock solution preparation, GDC-0077 is commonly dissolved in dimethyl sulfoxide (DMSO) to yield a concentrated stock (typically 10–50 mM). The stock solution should be aliquoted into single-use volumes to minimize freeze-thaw cycles, which can degrade compound potency over time. Working solutions for cell-based assays should be prepared by serial dilution into aqueous media immediately before use, keeping the final DMSO concentration ≤0.1% (v/v) to avoid solvent cytotoxicity.

Stability data for the reconstituted solution should be confirmed by the end user according to the specific storage conditions employed. Aladdin Scientific recommends consulting the product's Certificate of Analysis (CoA) for lot-specific purity data (HPLC and NMR) prior to initiating experiments.

Frequently asked questions

What makes GDC-0077 different from other PI3K inhibitors?

GDC-0077 is distinguished by its high selectivity for the PI3Kα isoform over PI3Kβ, PI3Kγ, and PI3Kδ. Unlike pan-PI3K inhibitors, this isoform selectivity reduces off-target effects in research models. Additionally, GDC-0077 has been reported to promote degradation of mutant PI3Kα protein, offering a potential mechanistic advantage over purely catalytic inhibitors.

In which cancer types is GDC-0077 most commonly studied?

GDC-0077 is most extensively studied in PIK3CA-mutant cancers, with particular focus on hormone receptor-positive, HER2-negative breast cancer. It has also been investigated in preclinical models of colorectal, endometrial, and other solid tumors harboring PIK3CA mutations, reflecting the broad prevalence of PI3Kα activation across oncology indications.

How should GDC-0077 be dissolved for cell-based assays?

GDC-0077 is typically dissolved in DMSO to prepare a concentrated stock solution (e.g., 10–50 mM). For cell-based experiments, the stock should be further diluted into aqueous culture medium to the desired working concentration, ensuring that the final DMSO content does not exceed 0.1% (v/v) to prevent solvent-related cytotoxic artifacts.

Is GDC-0077 suitable for in vivo mouse xenograft studies?

Yes, GDC-0077 has been evaluated in in vivo xenograft tumor models in preclinical literature. Formulation for in vivo use typically requires preparation in a vehicle compatible with oral or intravenous administration. Researchers should consult published protocols and validate the formulation in-house, as vehicle composition can influence bioavailability and tolerability.

Where can I find purity and characterization data for GDC-0077 from Aladdin Scientific?

Lot-specific purity and characterization data for GDC-0077 (SKU: G419993) are provided in the Certificate of Analysis (CoA) available through Aladdin Scientific. The CoA typically includes HPLC purity, NMR data, and mass spectrometry confirmation. Contact Aladdin Scientific customer service or visit the product page to request the CoA for your specific lot.

References

1. Juric D, et al. Phosphatidylinositol 3-kinase α–selective inhibition with alpelisib (BYL719) in PIK3CA-altered solid tumors. J Clin Oncol. 2018. [Background reference for PI3Kα isoform-selective inhibitor class context — not specific to GDC-0077; needs review]
2. Vanhaesebroeck B, et al. The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol. 2010;11(5):329-341. [General PI3K biology reference] doi:10.1038/nrm2882
3. Saura C, et al. Inavolisib (GDC-0077) in combination with palbociclib and fulvestrant in patients with PIK3CA-mutant, HR+/HER2− advanced breast cancer: clinical trial reference. [Specific trial details require verification]

Products are supplied for research and development use only. Not for use in humans, animals, diagnosis, or therapy.