GDC-0077 (RG6114) is a potent and selective PI3Kα inhibitor with an IC50 of 0.038nM. GDC-0077 is > 300-fold more selective for PI3Kα over the other class I PI3K isoforms (β, δ, and γ) 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[1]. GDC-0077 achieves precise targeting of PIK3CA-mutated tumors through a dual-action mechanism: selectively inhibiting PI3Kα activity and inducing the degradation of mutant p110α protein[2]. GDC-0077 is commonly used in the study of breast cancer.
GDC-0077 (0.3μM, 2 to 3 weeks) significantly inhibited proliferation in PIK3CA-mutant cell lines compared to the control. GDC-0077 combined with cobimetinib showed an increased cytotoxic response in four of five colorectal cancer cell lines[3].
GDC-0077 (25mg/kg/day, 25 days, i.g.) markedly enhanced the antitumor efficacy of the palbociclib-fulvestrant combination, elevating the mean tumor growth inhibition (TGI) from 71% to 106%[4].
References:
[1] Hong R, Edgar K, Song K, et al. Abstract PD4-14: GDC-0077 is a selective PI3Kalpha inhibitor that demonstrates robust efficacy in PIK3CA mutant breast cancer models as a single agent and in combination with standard of care therapies[J]. Cancer research, 2018, 78(4_Supplement): PD4-14-PD4-14.
[2] Zhu R, Zhang H, Zhang F. Mechanistic optimization of inavolisib combined with CDK4/6 inhibitors in the treatment of PIK3CA-mutated breast tumors[J]. Frontiers in Immunology, 2025, 16: 1693927.
[3] Song K W, Ong C C, Lin E, et al. KRAS codon-specific mutations differentially toggle PI3K pathway signaling and alter sensitivity to inavolisib (GDC-0077)[J]. Molecular Cancer Therapeutics, 2025, 24(12): 1890-1901.
[4] Song K W, Edgar K A, Hanan E J, et al. RTK-dependent inducible degradation of mutant PI3Kα drives GDC-0077 (Inavolisib) efficacy[J]. Cancer discovery, 2022, 12(1): 204-219.
GDC-0077 (RG6114)是一种高效且选择性的PI3Kα抑制剂，IC50值为0.038nM。GDC-0077对PI3Kα的选择性比其他I类PI3K亚型（β、δ和γ）高300倍以上，对PIK家族成员的选择性高2000倍以上。GDC-0077与PI3K的ATP结合位点结合，抑制PIP2磷酸化为PIP3[1]。GDC-0077通过双重作用机制实现对PIK3CA突变肿瘤的精准靶向：选择性抑制PI3Kα活性并诱导突变型p110α蛋白的降解[2]。GDC-0077常用于乳腺癌的研究。
与对照组相比，GDC-0077（0.3μM，2～3周）显著抑制了PIK3CA突变细胞系的增殖。GDC-0077与cobimetinib联合用药在五种结直肠癌细胞系中的四种中显示出增强的细胞毒性反应[3]。
GDC-0077（25mg/kg/天，25天，灌胃）显著增强了palbociclib-fulvestrant联合用药的抗肿瘤疗效，使平均肿瘤生长抑制率（TGI）从71%提高到106%[4]。