The Rational Design of Selective Benzoxazepin Inhibitors of the α‑Isoform of Phosphoinositide 3‑Kinase Culminating in the Identification of (<i>S</i>)‑2-((2-(1-Isopropyl‑1<i>H</i>‑1,2,4-triazol-5-yl)-5,6-dihydrobenzo[<i>f</i>]imidazo[1,2‑<i>d</i>][1,4]oxazepin-9-yl)oxy)propanamide (GDC-0326)

Inhibitors of the class I phosphoinositide 3-kinase (PI3K) isoform PI3Kα have received substantial attention for their potential use in cancer therapy. Despite the particular attraction of targeting PI3Kα, achieving selectivity for the inhibition of this isoform has proved challenging. Herein we report the discovery of inhibitors of PI3Kα that have selectivity over the other class I isoforms and all other kinases tested. In GDC-0032 (<b>3</b>, taselisib), we previously minimized inhibition of PI3Kβ relative to the other class I insoforms. Subsequently, we extended our efforts to identify PI3Kα-specific inhibitors using PI3Kα crystal structures to inform the design of benzoxazepin inhibitors with selectivity for PI3Kα through interactions with a nonconserved residue. Several molecules selective for PI3Kα relative to the other class I isoforms, as well as other kinases, were identified. Optimization of properties related to drug metabolism then culminated in the identification of the clinical candidate GDC-0326 (<b>4</b>)

Enhanced charge collection in MOF-525-PEDOT nanotube composites enable highly sensitive biosensing

[[abstract]]With the aim of a reliable biosensing exhibiting enhanced sensitivity and selectivity, this study demonstrates a dopamine (DA) sensor composed of conductive poly(3,4-ethylenedioxythiophene) nanotubes (PEDOT NTs) conformally coated with porphyrin-based metal-organic framework nanocrystals (MOF-525). The MOF-525 serves as an electrocatalytic surface, while the PEDOT NTs act as a charge collector to rapidly transport the electron from MOF nanocrystals. Bundles of these particles form a conductive interpenetrating network film that together: (i) improves charge transport pathways between the MOF-525 regions and (ii) increases the electrochemical active sites of the film. The electrocatalytic response is measured by cyclic voltammetry and differential pulse voltammetry techniques, where the linear concentration range of DA detection is estimated to be 2 × 10-6-270 × 10-6m and the detection limit is estimated to be 0.04 × 10-6m with high selectivity toward DA. Additionally, a real-time determination of DA released from living rat pheochromocytoma cells is realized. The combination of MOF5-25 and PEDOT NTs creates a new generation of porous electrodes for highly efficient electrochemical biosensing

Discovery and Preclinical Pharmacology of a Selective ATP-Competitive Akt Inhibitor (GDC-0068) for the Treatment of Human Tumors

The discovery and optimization of a series of 6,7-dihydro-5<i>H</i>-cyclopenta­[<i>d</i>]­pyrimidine compounds that are ATP-competitive, selective inhibitors of protein kinase B/Akt is reported. The initial design and optimization was guided by the use of X-ray structures of inhibitors in complex with Akt1 and the closely related protein kinase A. The resulting compounds demonstrate potent inhibition of all three Akt isoforms in biochemical assays and poor inhibition of other members of the cAMP-dependent protein kinase/protein kinase G/protein kinase C extended family and block the phosphorylation of multiple downstream targets of Akt in human cancer cell lines. Biological studies with one such compound, <b>28</b> (GDC-0068), demonstrate good oral exposure resulting in dose-dependent pharmacodynamic effects on downstream biomarkers and a robust antitumor response in xenograft models in which the phosphatidylinositol 3-kinase–Akt–mammalian target of rapamycin pathway is activated. <b>28</b> is currently being evaluated in human clinical trials for the treatment of cancer

Discovery of a Potent (4<i>R</i>,5<i>S</i>)‑4-Fluoro-5-methylproline Sulfonamide Transient Receptor Potential Ankyrin 1 Antagonist and Its Methylene Phosphate Prodrug Guided by Molecular Modeling

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel expressed in sensory neurons where it functions as an irritant sensor for a plethora of electrophilic compounds and is implicated in pain, itch, and respiratory disease. To study its function in various disease contexts, we sought to identify novel, potent, and selective small-molecule TRPA1 antagonists. Herein we describe the evolution of an <i>N</i>-isopropylglycine sulfonamide lead (<b>1</b>) to a novel and potent (4<i>R</i>,5<i>S</i>)-4-fluoro-5-methylproline sulfonamide series of inhibitors. Molecular modeling was utilized to derive low-energy three-dimensional conformations to guide ligand design. This effort led to compound <b>20</b>, which possessed a balanced combination of potency and metabolic stability but poor solubility that ultimately limited <i>in vivo</i> exposure. To improve solubility and <i>in vivo</i> exposure, we developed methylene phosphate prodrug <b>22</b>, which demonstrated superior oral exposure and robust <i>in vivo</i> target engagement in a rat model of AITC-induced pain