Crystal Structure of a Human K‑Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d

The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras­(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras­(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein–protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors

Second-Generation AUTACs for Targeted Autophagic Degradation

Targeted protein degradation via the ubiquitin-proteasome system has emerged as one of the most promising drug discovery modalities. Autophagy, another intracellular degradation system, can target a wide range of nonproteinous substrates as well as proteins, but its application to targeted degradation is still in its infancy. Our previous work revealed a relationship between guanine modification of cysteine residues on intracellular proteins and selective autophagy, resulting in the first autophagy-based degraders, autophagy-targeted chimeras (AUTACs). Based on the research background, all the reported AUTACs compounds contain cysteine as a substructure. Here, we examine the importance of this substructure by conducting SAR studies and report significant improvements in the degrader’s activity by replacing cysteine with other moieties. Several derivatives showed sub-μM range degrading activity, demonstrating the increased practical value of AUTACs

Second-Generation AUTACs for Targeted Autophagic Degradation

Targeted protein degradation via the ubiquitin-proteasome system has emerged as one of the most promising drug discovery modalities. Autophagy, another intracellular degradation system, can target a wide range of nonproteinous substrates as well as proteins, but its application to targeted degradation is still in its infancy. Our previous work revealed a relationship between guanine modification of cysteine residues on intracellular proteins and selective autophagy, resulting in the first autophagy-based degraders, autophagy-targeted chimeras (AUTACs). Based on the research background, all the reported AUTACs compounds contain cysteine as a substructure. Here, we examine the importance of this substructure by conducting SAR studies and report significant improvements in the degrader’s activity by replacing cysteine with other moieties. Several derivatives showed sub-μM range degrading activity, demonstrating the increased practical value of AUTACs

Discovery of a Novel Series of <i>N</i>‑Phenylindoline-5-sulfonamide Derivatives as Potent, Selective, and Orally Bioavailable Acyl CoA:Monoacylglycerol Acyltransferase‑2 Inhibitors

Acyl CoA:monoacylglycerol acyltransferase-2 (MGAT2) has attracted interest as a novel target for the treatment of obesity and metabolic diseases. Starting from <i>N</i>-phenylbenzenesulfonamide derivative <b>1</b> with moderate potency for MGAT2 inhibition, we explored an effective location of the hydrophobic group at the 1-position to enhance MGAT2 inhibitory activity. Shifting the hydrophobic group to the adjacent position followed by introduction of a bicyclic central core to restrict the substituent orientation produced <i>N</i>-phenylindoline-5-sulfonamide derivative <b>10b</b>, which displayed much improved potency, with an IC₅₀ value of 1.0 nM. This compound also exhibited excellent selectivity (greater than 30,000-fold) against related acyltransferases (MGAT3, DGAT1, DGAT2, and ACAT1). Subsequent optimization efforts were directed toward improving pharmacokinetic profiles, which resulted in the identification of 5-[(2,4-difluorophenyl)­sulfamoyl]-7-(2-oxopyrrolidin-1-yl)-<i>N</i>-[4-(trifluoromethyl)­phenyl]-2,3-dihydro-1<i>H</i>-indole-1-carboxamide (<b>24d</b>) endowed with potent MGAT2 inhibitory activity (IC₅₀ = 3.4 nM) and high oral bioavailability (<i>F</i> = 52%, mouse). In a mouse oral fat tolerance test, oral administration of this compound effectively suppressed the elevation of plasma triacylglycerol levels

Discovery of Novel 5‑(Piperazine-1-carbonyl)pyridin-2(1<i>H</i>)‑one Derivatives as Orally eIF4A3-Selective Inhibitors

Starting from our previous eIF4A3-selective inhibitor <b>1a</b>, a novel series of (piperazine-1-carbonyl)­pyridin-2­(1<i>H</i>)-one derivatives was designed, synthesized, and evaluated for identification of orally bioavailable probe molecules. Compounds <b>1o</b> and <b>1q</b> showed improved physicochemical and ADMET profiles, while maintaining potent and subtype-selective eIF4A3 inhibitory potency. In accord with their promising PK profiles and results from initial in vivo PD studies, compounds <b>1o</b> and <b>1q</b> showed antitumor efficacy with T/C values of 54% and 29%, respectively, without severe body weight loss. Thus, our novel series of compounds represents promising probe molecules for the in vivo pharmacological study of selective eIF4A3 inhibition

Synthesis, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities

Recently, we discovered 3-aminomethylquinoline derivative <b>1</b>, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of <b>1</b> was discontinued because <b>1</b> showed potent hERG K⁺ channel inhibition in a patch-clamp study. To decrease hERG K⁺ channel inhibition, experiments with ligand-based drug designs based on <b>1</b> and a docking study were conducted. Replacement of the terminal <i>p</i>-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)­ethyl]­amino group as the amine portion eliminated hERG K⁺ channel inhibitory activity in a patch-clamp study, leading to the discovery of <i>N</i>-{3-[(1<i>R</i>)-1-{[2-(acetylamino)­ethyl]­amino}­ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)­benzamide <b>(</b><i><b>R</b></i><b>)-10h</b>. The compound <b>(</b><i><b>R</b></i><b>)-10h</b> showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of <b>(</b><i><b>R</b></i><b>)-10h</b> was performed to determine the molecule’s absolute configuration