3TL5: Discovery Of Gdc-0980: A Potent, Selective, And Orally Available Class I Phosphatidylinositol 3-Kinase (Pi3k)MAMMALIAN TARGET OF RAPAMYCIN (Mtor) Kinase Inhibitor For The Treatment Of Cancer

The discovery of 2 (GDC-0980), a class I PI3K and mTOR kinase inhibitor for oncology indications, is described. mTOR inhibition was added to the class I PI3K inhibitor 1 (GDC-0941) scaffold primarily through the substitution of the indazole in 1 for a 2-aminopyrimidine. This substitution also increased the microsomal stability and the free fraction of compounds as evidenced through a pairwise comparison of molecules that were otherwise identical. Highlighted in detail are analogues of an advanced compound 4 that were designed to improve solubility, resulting in 2. This compound, is potent across PI3K class I isoforms with IC(50)s of 5, 27, 7, and 14 nM for PI3Kalpha, beta, delta, and gamma, respectively, inhibits mTOR with a K(i) of 17 nM yet is highly selective versus a large panel of kinases including others in the PIKK family. On the basis of the cell potency, low clearance in mouse, and high free fraction, 2 demonstrated significant efficacy in mouse xenografts when dosed as low as 1 mg/kg orally and is currently in phase I clinical trials for cancer.
PDB ID: 3TL5Download
MMDB ID: 94820
PDB Deposition Date: 2011/8/29
Updated in MMDB: 2011/11
Experimental Method:
x-ray diffraction
Resolution: 2.79  Å
Source Organism:
Similar Structures:
Biological Unit for 3TL5: monomeric; determined by author and by software (PISA)
Molecular Components in 3TL5
Label Count Molecule
Protein (1 molecule)
Phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit Gamma Isoform(Gene symbol: PIK3CG)
Molecule annotation
Chemical (1 molecule)
* Click molecule labels to explore molecular sequence information.

Citing MMDB