Optimization of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors, Leading to the Potent DS08701581.

Previously, we reported the new pyrido-pyridazinone template as a feline sarcoma-related (FER) tyrosine kinase inhibitor. Representative compound () showed strong enzyme inhibitory activity (IC50 = 0.5 nM), however, its antitumor effect was insufficient, probably due to poor solubility and resultant low bioavailability (BA).

Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation.

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.

Flexibility and Cell Permeability of Cyclic Ras-Inhibitor Peptides Revealed by the Coupled Nosé-Hoover Equation.

Quantifying the cell permeability of cyclic peptides is crucial for their rational drug design. However, the reasons remain unclear why a minor chemical modification, such as the difference between Ras inhibitors cyclorasin 9A5 and 9A54, can substantially change a peptide's permeability. To address this question, we performed enhanced sampling simulations of these two 11-mer peptides using the coupled Nosé-Hoover equation (cNH) we recently developed.

Discovery of DS79932728: A Potent, Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease.

Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently.

Discovery of novel histone lysine methyltransferase G9a/GLP (EHMT2/1) inhibitors: Design, synthesis, and structure-activity relationships of 2,4-diamino-6-methylpyrimidines.

The discovery and optimization of a novel series of G9a/GLP (EHMT2/1) inhibitors are described. Starting from known G9a/GLP inhibitor 5, efforts to explore the structure-activity relationship and optimize drug properties led to a novel compound 13, the side chain of which was converted to tetrahydroazepine. Compound 13 showed increased G9a/GLP inhibitory activity compared with compound 5.

Discovery of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors with Antitumor Activity.

To obtain a new anticancer drug, we focused on FER tyrosine kinase. Starting with high-throughput screening with our in-house chemical library, compound , which has a pyridine moiety, was found. Referring to their X-ray crystal structure with FES proto-oncogene tyrosine kinase, as a surrogate of FER followed by chemical modification including scaffold hopping of the pyridine template, we discovered pyrido-pyridazinone derivatives with potent FER kinase inhibitory activity.

A novel inhibitor stabilizes the inactive conformation of MAPK-interacting kinase 1.

Mitogen-activated protein kinase (MAPK)-interacting kinases 1 (Mnk1) and 2 (Mnk2) modulate translation initiation through the phosphorylation of eukaryotic translation initiation factor 4E, which promotes tumorigenesis. However, Mnk1 and Mnk2 are dispensable in normal cells, suggesting that the inhibition of Mnk1 and Mnk2 could be effective in cancer therapy. To provide a structural basis for Mnk1 inhibition, a novel Mnk1 inhibitor was discovered and the crystal structure of Mnk1 in complex with this inhibitor was determined.

Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor.

Polycomb repressive complex 2 (PRC2) methylates histone H3 lysine 27 and represses gene expression to regulate cell proliferation and differentiation. Enhancer of zeste homolog 2 (EZH2) or its close homolog EZH1 functions as a catalytic subunit of PRC2, so there are two PRC2 complexes containing either EZH2 or EZH1. Tumorigenic functions of EZH2 and its synthetic lethality with some subunits of SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complexes have been observed.

Discovery and structure-guided fragment-linking of 4-(2,3-dichlorobenzoyl)-1-methyl-pyrrole-2-carboxamide as a pyruvate kinase M2 activator.

Tumor cells switch glucose metabolism to aerobic glycolysis by expressing the pyruvate kinase M2 isoform (PKM2) in a low active form, providing glycolytic intermediates as building blocks for biosynthetic processes, and thereby supporting cell proliferation. Activation of PKM2 should invert aerobic glycolysis to an oxidative metabolism and prevent cancer growth. Thus, PKM2 has gained attention as a promising cancer therapy target.

Quantitative Structure-activity Relationship (QSAR) Models for Docking Score Correction.

In order to improve docking score correction, we developed several structure-based quantitative structure activity relationship (QSAR) models by protein-drug docking simulations and applied these models to public affinity data. The prediction models used descriptor-based regression, and the compound descriptor was a set of docking scores against multiple (∼600) proteins including nontargets. The binding free energy that corresponded to the docking score was approximated by a weighted average of docking scores for multiple proteins, and we tried linear, weighted linear and polynomial regression models considering the compound similarities.

Antitumor effects of novel highly hydrophilic and non-ATP-competitive MEK1/2 inhibitor, SMK-17.

The mitogen-activated protein kinase (MAPK) signal pathway plays a central role in regulating tumor cell proliferation, survival, and differentiation. The components of this pathway, Ras/Raf/MEK/ERK, are frequently activated in human cancers. Targeting this pathway is considered to be a promising anticancer strategy.

Discovery of imidazo[1,2-b]pyridazines as IKKβ inhibitors. Part 2: improvement of potency in vitro and in vivo.

We have increased the potency of imidazo[1,2-b]pyridazine derivatives as IKKβ inhibitors with two strategies. One is to enhance the activity in cell-based assay by adjusting the polarity of molecules to improve permeability. Another is to increase the affinity for IKKβ by the introduction of additional substituents based on the hypothesis derived from an interaction model study.

Discovery of imidazo[1,2-b]pyridazine derivatives as IKKbeta inhibitors. Part 1: Hit-to-lead study and structure-activity relationship.

Imidazo[1,2-b]pyridazine derivatives from high-throughput screening were developed as IKKbeta inhibitors. By the optimization of the 3- and 6-position of imidazo[1,2-b]pyridazine scaffold, cell-free IKKbeta inhibitory activity and TNFalpha inhibitory activity in THP-1 cell increased. Also, these compounds showed high kinase selectivity.