GDC-0941 Bimesylate

Description

Pictilisib (GDC-0941) is a potent inhibitor of PI3Kα/δ with IC50 of 3 nM in cell-free assays, with modest selectivity against p110β (11-fold) and p110γ (25-fold). Phase 2.

In vitro

GDC-0941 is equipotent against PI3Kα and PI3Kδ as well as PI3Kα mutants E545-K and H1047-R, displaying modest levels of selectivity against PI3Kβ (10-fold) and PI3Kγ (25-fold), and greater levels of selectivity against members of PI3K class II, III, and IV, including C2β, Vps34, DNA-PK, and mTOR. GDC-0941 potently inhibits the phosphorylation of Akt in U87MG, PC3, and MDA-MB-361 cells with IC50 of 46 nM, 37 nM, and 28 nM, respectively. GDC-0941 inhibits the proliferation of U87MG, A2780, PC3, and MDA-MB-361 cells with IC50 of 0.95 μM, 0.14 μM, 0.28 μM, and 0.72 μM, respectively. GDC-0941 treatment potently inhibits the proliferation of both trastuzumab-sensitive and-insensitive HER2-amplified cells with IC50 of 149-944 nM. GDC-0941 inhibits proliferation of HER2-amplified cells that harbor PIK3CA mutations with IC50 of <500 nM, and effectively inhibits both proliferation and viability of HER2-amplified breast cancer cells that are resistant to trastuzumab due to PTEN loss. GDC-0941 significantly inhibits the growth of HCT116, DLD1 and HT29 cells with GI50 of 1081 nM, 1070 nM and 157 nM, respectively. GDC-0941 inhibits tumor cell proliferation, induces apoptosis and suppresses centroblast population.

In vivo

Administration of GDC-0941 at 75 mg/kg/day displays significant inhibitory effect against established human U87MG glioblastoma xenografts in female NCr athymic mice, with tumor growth inhibition of 83%. Oral administration of GDC-0941 at 150 mg/kg/day inhibits the growth of HER2-amplified, trastuzumab-resistant MDA-MB-361.1 xenografts in mice, and significantly delays the tumor progression, in association with potent induced apoptosis in tumors. GDC-0941 (75 mg/kg/day) treatment for 2 weeks induces ~40% reduction in tumor volume of spontaneous B-cell follicular lymphomas developed in PTEN+/-LKB1+/hypo mice, accompanied by ablation of phosphorylation of Akt, S6K and SGK (serum and glucocorticoid protein kinase) protein kinases.

Chemical Properties

Off-White Solid

Uses

Potent inhibitor of Phosphatidylinositol 3-kinase (PI3K)

Biological Activity

gdc-0941 is a novel selective class i phosphatidylinositol-3-kinase (pi3k) inhibitor. activation of pi3k/akt signaling pathway is frequently associated with tumorigenesis. deregulation of this pathway occurs frequently with a variety of cancers and may contribute to the resistance to many anticancer agents. [1] developing novel small molecules that specifically block the pi3k/akt pathway may inhibit tumor growth. gdc-0941 is designed to bind the atp-binding pocket of pi3k and to prevent formation of phosphatidylinositol-3, 4, 5-triphosphate (pip3), a second messenger that transmits pi3k downstream signals. [2, 3] it binds to pi3k in an atp-competitive manner.gdc-0941 is a potent small-molecule thieno [3, 2-d] pyrimidine inhibitor of the class i pi3k. it is highly selective against isoforms p110( and p110( with ic50 of 3 nm, and moderately selective against isoforms p110( and p110( with ic50s of 33 nm and 75 nm, respectively.gdc-0941 inhibits cell proliferation in vitro and in vivo. it causes growth inhibition in a variety of cancer cell lines, including a2780, mda-mb-361, pc3, and u87mg. [2] it also inhibits the growth of trastuzumab–sensitive and –resistant her2-amplied cancer cells which harbor p110( mutations or pten loss. [4] gdc-0941 also reduces tumor volume in different xenograft models. [4]gdc-0941 can be taken orally.

in vivo

target

PI3Kα

IC 50

p110α: 3 nM (IC₅₀); p110α-H1047R: 3 nM (IC₅₀); p110α-E545K: 3 nM (IC₅₀); p110δ: 3 nM (IC₅₀); p110β: 33 nM (IC₅₀); p110γ: 75 nM (IC₅₀); mTOR: 0.58 μM (Ki); DNA-PK: 1.23 μM (IC₅₀); Autophagy

References

[1]yuan tl, cantley lc. pi3k pathway alterations in cancer: variations on a theme. oncogene. 2008;27:5497-5510.
[2]folkes aj, ahmadi k, alderton wk, et al. the identification of 2-(1h-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (gdc-0941) as a potent, selective, orally bioavailable inhibitor of class i pi3 kinase for the treatment of cancer. j med chem. 2008; 51: 5522-5532.
[3]knight za, shokat km. chemically targeting the pi3k family. biochem soc trans. 2007; 35: 245-249.
[4]junttila tt, akita rw, parsons k, fields c, lewis phillips gd, friedman ls, sampath d, sliwkowski mx. ligand-independent her2/her3/pi3k complex is disrupted by trastuzumab and is effectively inhibited by the pi3k inhibitor gdc-0941. br j cancer. 2011; 104(7): 1116-25.