GDC-0449 (Vismodegib)

GDC-0449 (Vismodegib) is an orally active and highly selective Smoothened (SMO) receptor inhibitor that suppresses the Hedgehog signaling pathway with an IC₅₀ value of 3.0nM^[1]. It also inhibits the activity of P-gp and ABCG2, with IC₅₀ values of 3.0μM and 1.4μM, respectively^[2]. As a key component of the Hedgehog pathway, SMO is effectively inhibited by GDC-0449, which blocks the activation of downstream GLI transcription factors and subsequent target gene expression induced by Hedgehog ligands^[3,4]. GDC-0449 is commonly used in basic research and drug development for cancers such as basal cell carcinoma and medulloblastoma^[5], as well as in functional studies of the Hedgehog pathway in processes including cell growth, differentiation, and tumorigenesis^[6].

In vitro, treatment of HCC (lung adenocarcinoma) and H1339 (small cell lung carcinoma) cells with GDC-0449 (25μM or 50μM) for 4 days resulted in concentration-dependent inhibition of cell growth^[7]. Furthermore, exposure of human breast cancer cell lines (MCF-7, T47-D, MDA-MB-231, MDA-MB-468, MDA-MB-453, BT-474, and SK-BR-3) as well as murine TUBO cells to GDC-0449 (3-12μM) for 48, 72, 96h, or 6 days led to concentration- and time-dependent reductions in cell viability across all cell lines. However, the effective concentration was relatively high (≥12μM), and the onset of action was slow, requiring 72h to 6 days to achieve significant effects^[8].

In vivo, oral administration of GDC-0449 (2mg/mouse; 3 times per week) to female BALB/c mice subcutaneously inoculated with TUBO breast cancer cells significantly reduced the mean tumor volume compared to the control group (513mm³ vs. 1070mm³) after three weeks of treatment^[8]. In a Ptch^⁺/⁻ mouse allograft model of medulloblastoma, oral treatment with GDC-0449 (25-75mg/kg/day) for 14 days induced complete tumor regression, with maximal antitumor effects achieved at doses ≥ 25mg/kg^[9].

References:
[1] SCALES S J, DE SAUVAGE F J. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy[J]. Trends in Pharmacological Sciences, 2009, 30(6): 303-312.
[2] ZHANG Y, LATERRA J, POMPER M G. Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp[J]. Neoplasia, 2009, 11(1): 96-101.
[3] INGHAM P W, MCMAHON A P. Hedgehog signaling in animal development: paradigms and principles[J]. Genes & Development, 2001, 15(23): 3059-3087.
[4] RUBIN L L, DE SAUVAGE F J. Targeting the Hedgehog pathway in cancer[J]. Nature Reviews Drug Discovery, 2006, 5(12): 1026-1033.
[5] LORUSSO P M, RUDIN C M, REDDY J C, et al. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors[J]. Clinical Cancer Research, 2011, 17(8): 2502-2511.
[6] YAUCH R L, GOULD S E, SCALES S J, et al. A paracrine requirement for hedgehog signalling in cancer[J]. Nature, 2008, 455(7211): 406-410.
[7] TIAN F, SCHRÖDL K, KIEFL R, et al. The hedgehog pathway inhibitor GDC-0449 alters intracellular Ca2+ homeostasis and inhibits cell growth in cisplatin-resistant lung cancer cells[J]. Anticancer Research, 2012, 32(1): 89-94.
[8] BENVENUTO M, MASUELLI L, DE SMAELE E, et al. In vitro and in vivo inhibition of breast cancer cell growth by targeting the Hedgehog/GLI pathway with SMO (GDC-0449) or GLI (GANT-61) inhibitors[J]. Oncotarget, 2016, 7(8): 9250.
[9] WONG H, ALICKE B, WEST K A, et al. Pharmacokinetic-pharmacodynamic analysis of vismodegib in preclinical models of mutational and ligand-dependent Hedgehog pathway activation[J]. Clinical Cancer Research, 2011, 17(14): 4682-4692.

GDC-0449 (Vismodegib)是一种具有口服活性和高效选择性的Smoothened（SMO）受体抑制剂，可抑制Hedgehog信号通路，IC₅₀值为3.0nM^[1]。同时，也可抑制P-gp和ABCG2的活性，IC₅₀值分别为3.0μM和1.4μM^[2]。SMO是Hedgehog信号通路的关键成分，小分子抑制剂GDC-0449通过抑制SMO的活性，阻止了Hedgehog配体触发的下游GLI转录因子激活及其靶基因表达^[3,4]。GDC-0449通常用于癌症（如基底细胞癌和髓母细胞瘤）的基础研究与药物开发^[5]，也广泛应用于Hedgehog通路在细胞生长、分化和肿瘤发生等中的功能学研究^[6]。

在体外，GDC-0449（25μM或50μM）处理HCC（adenocarcinoma of the lung）和H1339（small cell lung carcinoma）细胞4天，能浓度依赖性地抑制HCC和H1339细胞的生长^[7]。GDC-0449（3-12μM）处理人源MCF-7、T47-D、MDA-MB-231、MDA-MB-468、MDA-MV-453、BT-474和SK-BR-3和鼠源TUBO的乳腺癌细胞48，72，96h或6天，可浓度和时间依赖性地降低所有细胞系的存活率，但有效浓度较高（12μM），且起效速度较慢（需72h至6天）^[8]。

在体内，GDC-0449（2mg/只；每周3次）通过口服治疗已皮下接种TUBO乳腺癌细胞的BALB/c雌性小鼠，治疗3周后，GDC-0449治疗组的小鼠平均肿瘤体积较对照组显著减小（513 compared with 1070mm³）^[8]。GDC-0449（25-75mg/kg/day）口服治疗髓母细胞瘤同种异体移植的Ptch^+/-小鼠14天可引起肿瘤完全消退，在≥25mg/kg时效应达到饱和^[9]。