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The potent BACE1 inhibitor LY2886721 elicits robust central A? pharmacodynamic responses in mice, dogs, and humans.

ABSTRACT: BACE1 is a key protease controlling the formation of amyloid ?, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against key off-target proteases, which efficiently translates in vitro activity into robust in vivo amyloid ? lowering in nonclinical animal models. Similar potent and persistent amyloid ? lowering was observed in plasma and lumbar CSF when single and multiple doses of LY2886721 were administered to healthy human subjects. Collectively, these data add support for BACE1 inhibition as an effective means of amyloid lowering and as an attractive target for potential disease modification therapy in AD.

SUBMITTER: May PC

PROVIDER: S-EPMC6605527 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans.

May Patrick C PC Willis Brian A BA Lowe Stephen L SL Dean Robert A RA Monk Scott A SA Cocke Patrick J PJ Audia James E JE Boggs Leonard N LN Borders Anthony R AR Brier Richard A RA Calligaro David O DO Day Theresa A TA Ereshefsky Larry L Erickson Jon A JA Gevorkyan Hykop H Gonzales Celedon R CR James Douglas E DE Jhee Stanford S SS Komjathy Steven F SF Li Linglin L Lindstrom Terry D TD Mathes Brian M BM Martényi Ferenc F Sheehan Scott M SM Stout Stephanie L SL Timm David E DE Vaught Grant M GM Watson Brian M BM Winneroski Leonard L LL Yang Zhixiang Z Mergott Dustin J DJ

The Journal of neuroscience : the official journal of the Society for Neuroscience 20150101 3

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 active site inhibitor that reached phase 2 clinical trials in AD. LY2886721 has high selectivity against ...[more]

PMID: 25609634

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Project description:Purpose: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase, is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. Experimental Design: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. Results: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer and PTEN-deficient MES-SA uterine tumor xenografts was demonstrated. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 due to compensatory feedback loops was observed. Conclusions: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which demonstrates a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human Phase I trial. The PTEN-deficient U87MG glioblastoma cell line was treated for 6 hours with vehicle control (DMSO) or to different concentrations of AT13148 and CCT128930 (0.1uM, 1xGI50 and 3XGI50).

Dataset Information

The potent BACE1 inhibitor LY2886721 elicits robust central A? pharmacodynamic responses in mice, dogs, and humans.

Publications

The potent BACE1 inhibitor LY2886721 elicits robust central Aβ pharmacodynamic responses in mice, dogs, and humans.

Similar Datasets

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