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. 2016 Feb 16;7(4):351-6.
doi: 10.1021/acsmedchemlett.6b00005. eCollection 2016 Apr 14.

Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

Timothy P Heffron  1 , Chudi O Ndubaku  1 , Laurent Salphati  1 , Bruno Alicke  1 , Jonathan Cheong  1 , Joy Drobnick  1 , Kyle Edgar  1 , Stephen E Gould  1 , Leslie B Lee  1 , John D Lesnick  1 , Cristina Lewis  1 , Jim Nonomiya  1 , Jodie Pang  1 , Emile G Plise  1 , Steve Sideris  1 , Jeffrey Wallin  1 , Lan Wang  1 , Xiaolin Zhang  1 , Alan G Olivero  1
Affiliations

Discovery of Clinical Development Candidate GDC-0084, a Brain Penetrant Inhibitor of PI3K and mTOR

Timothy P Heffron et al. ACS Med Chem Lett. .

Abstract

Inhibition of phosphoinositide 3-kinase (PI3K) signaling is an appealing approach to treat brain tumors, especially glioblastoma multiforme (GBM). We previously disclosed our successful approach to prospectively design potent and blood-brain barrier (BBB) penetrating PI3K inhibitors. The previously disclosed molecules were ultimately deemed not suitable for clinical development due to projected poor metabolic stability in humans. We, therefore, extended our studies to identify a BBB penetrating inhibitor of PI3K that was also projected to be metabolically stable in human. These efforts required identification of a distinct scaffold for PI3K inhibitors relative to our previous efforts and ultimately resulted in the identification of GDC-0084 (16). The discovery and preclinical characterization of this molecule are described within.

Keywords: CNS; PI3K; blood−brain barrier penetration; kinase inhibitor; oncology.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Scheme 1
Scheme 1. Synthetic Route to Obtain Tricyclic Purine-Based Brain Penetrant PI3K Inhibitor 16
Figure 1
Figure 1
CNS penetration of 16 in rat and mouse. [Brain]/[Plasma] ratios determined after oral dose of 16 to female CD-1 mice or male Sprague–Dawley rats as an MCT suspension. *[Brain]u and [Plasma]u refer to the unbound concentration measured in the brain and plasma, respectively. **[CSF] refers to the concentration measured in the cerebral spinal fluid. aDetermined to be identical at both 1 and 6 h after administration of 25 mg/kg 16 to female CD-1 mice. The [Brain]/[Plasma] ratios are the mean values from 3 animals per time point. bDetermined after administration of 15 mg/kg 16 to male Sprague–Dawley rats. [Brain]/[Plasma] determined for 1 animal at each of 0.25 and 2 h and 3 at 8 h. Data reported are the range across the three time points (average of the 3 animals at 8 h). c[CSF] determined for 1 animal at each of 0.25 and 2 h and 3 at 8 h. Data reported are the range across the three time points (average of the 3 animals at 8 h).
Figure 2
Figure 2
Inhibition of p-AKT by 16 in normal mouse brain tissue along with corresponding brain and unbound brain concentrations. *Significantly different from untreated control. p < 0.05, t test. [Brain] determined after 25 mg/kg oral dose of 16 female CD-1 mice as an MCT suspension. [Brain]u refers to the unbound concentration measured in the brain. Data are reported as mean values ± SD from 3 animals per time point.
Figure 3
Figure 3
In vivo efficacy of 16 versus U87 MG/M human glioblastoma xenografts. Female NCr nude mice bearing subcutaneous tumors were administered escalating doses of 16 orally as a suspension in vehicle (0.5% methylcellulose/0.2% Tween-80) or vehicle once daily (QD) for 23 days. Changes in tumor volumes over time by dose for each compound are depicted as cubic spline fits generated via Linear Mixed Effects analysis of log-transformed volumes.
Figure 4
Figure 4
Effect of 16 on the PD marker pAKT in the U87 MG/M human glioblastoma xenograft model after 24 days of continuous dosing. Tumors were excised from animals 1 and 4 h after the last administered dose on day 24 and processed for analysis of pAKT as described in the Supporting Information. Indicated values are the means for groups of 3 animals, and error bars indicate ± standard error of the mean. Levels of pAkt (Ser473) and total Akt were measured by electrochemiluminescence using Meso Scale Discovery according to manufacturer’s instructions (Gaithersburg, MD).
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