Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 4. Exploration of a Novel Binding Pocket

Structure–activity relationship investigations conducted at the 5-position of the <i>N</i>-pyridine ring of a series of <i>N</i>-arylsulfonyl-<i>N</i>′-2-pyridinyl-piperazines led to the identification of a novel bis-pyridinyl piperazine sulfonamide (<b>51</b>) that was a potent disruptor of the glucokinase–glucokinase regulatory protein (GK–GKRP) interaction. Analysis of the X-ray cocrystal of compound <b>51</b> bound to hGKRP revealed that the 3-pyridine ring moiety occupied a previously unexplored binding pocket within the protein. Key features of this new binding mode included forming favorable contacts with the top face of the Ala27-Val28-Pro29 (“shelf region”) as well as an edge-to-face interaction with the Tyr24 side chain. Compound <b>51</b> was potent in both biochemical and cellular assays (IC₅₀ = 0.005 μM and EC₅₀ = 0.205 μM, respectively) and exhibited acceptable pharmacokinetic properties for in vivo evaluation. When administered to <i>db/db</i> mice (100 mg/kg, po), compound <b>51</b> demonstrated a robust pharmacodynamic effect and significantly reduced blood glucose levels up to 6 h postdose

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 5. A Novel Aryl Sulfone Series, Optimization Through Conformational Analysis

The glucokinase–glucokinase regulatory protein (GK-GKRP) complex plays an important role in controlling glucose homeostasis in the liver. We have recently disclosed a series of arylpiperazines as in vitro and in vivo disruptors of the GK-GKRP complex with efficacy in rodent models of type 2 diabetes mellitus (T2DM). Herein, we describe a new class of aryl sulfones as disruptors of the GK-GKRP complex, where the central piperazine scaffold has been replaced by an aromatic group. Conformational analysis and exploration of the structure–activity relationships of this new class of compounds led to the identification of potent GK-GKRP disruptors. Further optimization of this novel series delivered thiazole sulfone <b>93</b>, which was able to disrupt the GK-GKRP interaction in vitro and in vivo and, by doing so, increases cytoplasmic levels of unbound GK

Small Molecule Disruptors of the Glucokinase–Glucokinase Regulatory Protein Interaction: 2. Leveraging Structure-Based Drug Design to Identify Analogues with Improved Pharmacokinetic Profiles

In the previous report, we described the discovery and optimization of novel small molecule disruptors of the GK-GKRP interaction culminating in the identification of <b>1</b> (AMG-1694). Although this analogue possessed excellent in vitro potency and was a useful tool compound in initial proof-of-concept experiments, high metabolic turnover limited its advancement. Guided by a combination of metabolite identification and structure-based design, we have successfully discovered a potent and metabolically stable GK-GKRP disruptor (<b>27</b>, AMG-3969). When administered to <i>db</i>/<i>db</i> mice, this compound demonstrated a robust pharmacodynamic response (GK translocation) as well as statistically significant dose-dependent reductions in fed blood glucose levels

Discovery and Structure-Guided Optimization of Diarylmethanesulfonamide Disrupters of Glucokinase–Glucokinase Regulatory Protein (GK–GKRP) Binding: Strategic Use of a N → S (n_N → σ*_S–X) Interaction for Conformational Constraint

The HTS-based discovery and structure-guided optimization of a novel series of GKRP-selective GK–GKRP disrupters are revealed. Diarylmethane­sulfonamide hit <b>6</b> (hGK–hGKRP IC₅₀ = 1.2 μM) was optimized to lead compound <b>32</b> (AMG-0696; hGK–hGKRP IC₅₀ = 0.0038 μM). A stabilizing interaction between a nitrogen atom lone pair and an aromatic sulfur system (n_N → σ*_S–X) in <b>32</b> was exploited to conformationally constrain a biaryl linkage and allow contact with key residues in GKRP. Lead compound <b>32</b> was shown to induce GK translocation from the nucleus to the cytoplasm in rats (IHC score = 0; 10 mg/kg po, 6 h) and blood glucose reduction in mice (POC = −45%; 100 mg/kg po, 3 h). X-ray analyses of <b>32</b> and several precursors bound to GKRP were also obtained. This novel disrupter of GK–GKRP binding enables further exploration of GKRP as a potential therapeutic target for type II diabetes and highlights the value of exploiting unconventional nonbonded interactions in drug design

Oxopyrido[2,3‑<i>d</i>]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors

In nonsmall cell lung cancer (NSCLC), the threonine⁷⁹⁰–methionine⁷⁹⁰ (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido­[2,3-<i>d</i>]­pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound <b>24</b> which potently inhibits gefitinib-resistant EGFR^L858R,T790M with 100-fold selectivity over wild-type EGFR. Compound <b>24</b> displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR^L858R,T790M driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR

Structure-Based Design of a Novel Series of Potent, Selective Inhibitors of the Class I Phosphatidylinositol 3-Kinases

A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor <b>5</b>, a structure-based approach was used to improve potency and selectivity, resulting in the identification of <b>54</b> as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound <b>54</b> demonstrated a robust PD–PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway

Selective Class I Phosphoinositide 3‑Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511

The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 4-(2-((6-methoxypyridin-3-yl)­amino)-5-((4-(methylsulfonyl)­piperazin-1-yl)­methyl)­pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (<b>1</b>). In this paper, we describe the optimization of compound <b>1</b>, which led to the design and synthesis of pyridyltriazine <b>31</b>, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound <b>31</b> was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound <b>31</b> was selected for further evaluation as a clinical candidate and was designated AMG 511