Saturday, May 2, 2015

Drugs in Clinical Pipeline: Pictilisib

Pictilisib [4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine] is an oral, ATP-competitive inhibitor of PI3K family of kinases. The compound is equipotent against p110a and p110δ, while displaying modest levels of selectivity against p110b (10-fold) and p110γ (25-fold). However, greater levels of selectivity are observed for Pictilisib when tested against members of PI3K classes II, III, and IV, including C2b (IC50 = 65 nM), Vps34 (IC50 greater than 10 uM), DNA-PK (IC50 = 1.23 uM), and mTOR (IC50 = 58 nM) [1].

The activity of Pictilisib is as follows: 

IC50 (p110a enzyme assay) = 3 nM 
IC50 (p110δ enzyme assay) = 3 nM
IC50 (p110b enzyme assay) = 33 nM
IC50 (p110γ enzyme assay) = 75 nM

Common Name: Pictilisib
Synonyms:  GDC-0941; GDC 0941; GDC0941; RG7321; RG-7321; RG 7321; GNE0941; GNE-0941; GNE 0941; Pictrelisib
IUPAC Name: 4-(2-(1H-indazol-4-yl)-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine
CAS Number: 957054-30-7
Mechanism of Action: Kinase Inhibitor; PI3K Inhibitor; pan-PI3K Inhibitor
Indication: Various Cancers; Multiple Myeloma; Advanced Tumors
Development Stage: Phase II
Company: Genentech Inc

Pictilisib was also tested against two of the p110a mutant enzymes detected in human cancer. E545-K, which is a hotspot mutation in the helical domain and H1047-R, a hotspot mutation located in the C-terminal portion of the kinase domain, have both been shown to have elevated lipid kinase activity relative to the wild type and represent two of the three hotspots responsible for 80% of p110a mutations. Pictilisib was found to be equipotent against both mutants when compared to the wild type protein.

Experiments have also indicated that Pictilisib is a potent, ATP competitive inhibitor of p110a with a Ki value of 10.2 ± 4.4 nM. Pictilisib displayed outstanding selectivity for the PIK family kinases over a panel of 228 kinases in the KinaseProfiler panel from Millipore (formerly Upstate Biotechnologies). Of the 228 kinases tested, only two displayed greater than 50% inhibition by 1 µM. The human tyrosine kinase Flt3 displayed 59% inhibition by the test article, and the human kinase TrkA displayed 61% inhibition by 1 µM. The IC50 value of Pictilisib for inhibition of TrkA was subsequently determined to be 2.85 µM. Thus, Pictilisib demonstrates at least 300-fold selectivity for inhibition of p110a/p85a over other assayable kinases [1].

Acceptable oral bioavailability was achieved in all species tested, including mouse (77%), rat (30%), dog (71%), and monkey (20%) [1,2].

Phase I Study

Pictilisib was evaluated in human dose-escalation trial for safety, tolerability, maximal-tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, pharmacodynamics, and preliminary clinical activity [3].


Sixty patients with solid tumors received pictilisib at 14 dose levels from 15 to 450 mg once-daily, initially on days 1 to 21 every 28 days and later, using continuous dosing for selected dose levels. Pharmacodynamic studies incorporated (18)F-FDG-PET, and assessment of phosphorylated AKT and S6 ribosomal protein in platelet-rich plasma (PRP) and tumor tissue.


Pictilisib was well tolerated. The most common toxicities were grade 1-2 nausea, rash, and fatigue, whereas the DLT was grade 3 maculopapular rash (450 mg, 2 of 3 patients; 330 mg, 1 of 7 patients). The pharmacokinetic profile was dose-proportional and supported once-daily dosing. Levels of phosphorylated serine-473 AKT were suppressed greater than 90% in PRP at 3 hours after dose at the MTD and in tumor at pictilisib doses associated with AUC greater than 20 h·µmol/L. Significant increase in plasma insulin and glucose levels, and greater than 25% decrease in (18)F-FDG uptake by PET in 7 of 32 evaluable patients confirmed target modulation. Pictilisib was safely administered with a dose-proportional pharmacokinetic profile, on-target pharmacodynamic activity at dose levels of 100 mg and signs of antitumor activity. The recommended phase II dose was continuous dosing at 330 mg once-daily.

1. Folkes, A. J.; 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(18), 5522-5532.
2. Salphati, L.; et. al. Preclinical pharmacokinetics of the novel PI3K inhibitor GDC-0941 and prediction of its pharmacokinetics and efficacy in human. Xenobiotica 2011, 41(12), 1088-1099.
3. Sarker, D.; et. al. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res 2015, 21(1), 77-86.