File(s) not publicly available
Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer
journal contribution
posted on 2023-06-08, 21:50 authored by Daniel P Sutherlin, Linda Bao, Megan Berry, Georgette Castanedo, Irina Chuckowree, Jenna Dotson, Adrian Folks, Lori Friedman, Richard Goldsmith, Janet Gunzner, Timothy Heffron, John Lesnick, Cristina Lewis, Simon Mathieu, Jeremy Murray, Jim Nonomiya, Jodie Pang, Niel Pegg, Wei Wei Prior, Lionel Rouge, Laurent Salphati, Deepak Sampath, Qingping Tian, Vickie Tsui, Nan Chi Wan, Shumei Wang, BinQing Wei, Christian Wiesmann, Ping Wu, Bing-Yan Zhu, Alan OliveroThe 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 PI3Ka, ß, d, and ?, 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.
History
Publication status
- Published
Journal
Journal of Medicinal ChemistryISSN
0022-2623Publisher
American Chemical SocietyExternal DOI
Issue
21Volume
54Page range
7579-7587Department affiliated with
- Chemistry Publications
Full text available
- No
Peer reviewed?
- Yes
Legacy Posted Date
2015-07-23Usage metrics
Categories
No categories selectedKeywords
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC