title: 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.
abstract: 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 PI3Kα, β, δ, and γ, 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.
authors: Genentech, Inc., South San Francisco, CA 94080, USA. sutherlin.dan@gene.com
authors: Daniel P
authors: DP
authors: Sutherlin
authors: Linda
authors: L
authors: Bao
authors: Megan
authors: M
authors: Berry
authors: Georgette
authors: G
authors: Castanedo
authors: Irina
authors: I
authors: Chuckowree
authors: Jenna
authors: J
authors: Dotson
authors: Adrian
authors: A
authors: Folks
authors: Lori
authors: L
authors: Friedman
authors: Richard
authors: R
authors: Goldsmith
authors: Janet
authors: J
authors: Gunzner
authors: Timothy
authors: T
authors: Heffron
authors: John
authors: J
authors: Lesnick
authors: Cristina
authors: C
authors: Lewis
authors: Simon
authors: S
authors: Mathieu
authors: Jeremy
authors: J
authors: Murray
authors: Jim
authors: J
authors: Nonomiya
authors: Jodie
authors: J
authors: Pang
authors: Niel
authors: N
authors: Pegg
authors: Wei Wei
authors: WW
authors: Prior
authors: Lionel
authors: L
authors: Rouge
authors: Laurent
authors: L
authors: Salphati
authors: Deepak
authors: D
authors: Sampath
authors: Qingping
authors: Q
authors: Tian
authors: Vickie
authors: V
authors: Tsui
authors: Nan Chi
authors: NC
authors: Wan
authors: Shumei
authors: S
authors: Wang
authors: Binqing
authors: B
authors: Wei
authors: Christian
authors: C
authors: Wiesmann
authors: Ping
authors: P
authors: Wu
authors: Bing-Yan
authors: BY
authors: Zhu
authors: Alan
authors: A
authors: Olivero
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors*; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D014183:Transplantation, Heterologous
chemical_list: C569670:1-(4-((2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholinothieno(3,2-d)pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one; D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007527:Isoenzymes; D011743:Pyrimidines; D058534:Class I Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases