Characterization of LY3023414, a Novel PI3K/mTOR Dual Inhibitor Eliciting Transient Target Modulation to Impede Tumor Growth.

The PI3K/AKT/mTOR pathway is among the most frequently altered pathways in cancer cell growth and survival. LY3023414 is a complex fused imidazoquinolinone with high solubility across a wide pH range designed to inhibit class I PI3K isoforms and mTOR kinase. Here, we describe the in vitro and in vivo activity of LY3023414. LY3023414 was highly soluble at pH 2-7. In biochemical testing against approximately 266 kinases, LY3023414 potently and selectively inhibited class I PI3K isoforms, mTORC1/2, and DNA-PK at low nanomolar concentrations. In vitro, inhibition of PI3K/AKT/mTOR signaling by LY3023414 caused G1 cell-cycle arrest and resulted in broad antiproliferative activity in cancer cell panel screens. In vivo, LY3023414 demonstrated high bioavailability and dose-dependent dephosphorylation of PI3K/AKT/mTOR pathway downstream substrates such as AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, reflecting the drug's half-life of 2 hours. Of note, equivalent total daily doses of LY3023414 given either once daily or twice daily inhibited tumor growth to similar extents in multiple xenograft models, indicating that intermittent target inhibition is sufficient for antitumor activity. In combination with standard-of-care drugs, LY3023414 demonstrated additive antitumor activity. The novel, orally bioavailable PI3K/mTOR inhibitor LY3023414 is highly soluble and exhibits potent in vivo efficacy via intermittent target inhibition. It is currently being evaluated in phase I and II trials for the treatment of human malignancies. Mol Cancer Ther; 15(10); 2344-56. ©2016 AACR.

P3 cap modified Phe*-Ala series BACE inhibitors.

With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).

P1 and P3 optimization of novel bicycloproline P2 bearing tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.

With the aim of discovering potent and selective HCV protease inhibitors, we synthesized and evaluated a series of 1a based tetrapeptidyl ketoamides with additional modification(s) at P1', P1, and P3 positions. As a result of this effort, we found that replacement of the P3 valine with tert-leucine resulted in the discovery of a series of inhibitors (e.g., 3a, 3c, and 4c) endowed with improved enzyme and/or cellular activity relative to 1a. When dosed to F-344 rats orally at 50mg/kg, 3a achieved 2.5x higher liver and plasma exposure in comparison to that detected with 1a.

P4 and P1' optimization of bicycloproline P2 bearing tetrapeptidyl alpha-ketoamides as HCV protease inhibitors.

With the aim of improving HCV protease inhibitors reported in our previous manuscripts, we synthesized and evaluated a series of 1a-based tetrapeptidyl alpha-ketoamides with additional P4 modification. The promising analog discovered through this SAR, 5a, was further derivatized at P1' or P1 position. As a result of these efforts, we found that replacement of the P4 valine as seen in 1a with cyclohexylglycine (Chg) resulted in the discovery of 5a, 5c, and 5e endowed with improved cellular activity in comparison to 1a.

P4 cap modified tetrapeptidyl alpha-ketoamides as potent HCV NS3 protease inhibitors.

We describe herein the design, syntheses, and biological evaluation of new series of P4 tetrazole and adipic acid, ester, amide capped tetrapeptidyl alpha-ketoamide based HCV protease inhibitors.

Discovery of a novel bicycloproline P2 bearing peptidyl alpha-ketoamide LY514962 as HCV protease inhibitor.

We describe herein the design, syntheses and evaluation of a number of bicycloproline P2 bearing HCV protease inhibitors endowed with impressive enzyme potency, enzyme selectivity, cellular activity and favorable ADME profiles.