Discovery and Rational Design of Pteridin-7(8<i>H</i>)‑one-Based Inhibitors Targeting FMS-like Tyrosine Kinase 3 (FLT3) and Its Mutants

FLT3 has been validated as a therapeutic target for the treatment of acute myeloid leukemia (AML). In this paper, we describe for the first time, pteridin-7­(8<i>H</i>)-one as a scaffold for potent FLT3 inhibitors derived from structural optimizations on irreversible EGFR inhibitors. The representative inhibitor (<b>31</b>) demonstrates single-digit nanomolar inhibition against FLT3 and subnanomolar <i>K</i>_D for drug-resistance FLT3 mutants. In profiling of the in vitro tumor cell lines, it shows good selectivity against AML cells harboring FLT3-ITD mutations over other leukemia and solid tumor cell lines. The mechanism of action study illustrates that pteridin-7­(8<i>H</i>)-one derivatives suppress the phosphorylation of FLT3 and its downstream pathways, thereby inducing G₀/G₁ cell cycle arrest and apoptosis in AML cells. In in vivo studies, <b>31</b> significantly suppresses the tumor growth in MV4–11 xenograft model. Overall, we provide a structurally distinct chemical scaffold with which to develop FLT3 mutants-selective inhibitors for AML treatment

Discovery of Pteridin-7(8<i>H</i>)‑one-Based Irreversible Inhibitors Targeting the Epidermal Growth Factor Receptor (EGFR) Kinase T790M/L858R Mutant

The EGFR T790M variant is an important mutation, resulting in approximately 50% of the clinically acquired resistance to approved EGFR inhibitors. Starting with a previously reported pyrimidine-based EGFR inhibitor, a novel pteridin-7­(8<i>H</i>)-one scaffold with a high 3D similarity was found and transformed into irreversible inhibitors of the EGFR T790M mutant. The most potent compounds, <b>3q</b> and <b>3x</b>, exhibited excellent enzyme inhibitory activities, with subnanomolar IC₅₀ values for both the wild-type and T790M/L858R double mutant EGFRs, as well as potent cellular antiproliferative activities against both gefitinib-sensitive and -resistant cancer cell lines. The in vivo antitumor efficacy study demonstrated that compound <b>3x</b> significantly inhibited tumor growth and induced tumor stasis in an EGFR-T790M/L858R-driven human nonsmall-cell lung cancer xenograft mouse model. This work demonstrated the utility of this sophisticated computational design strategy for fast 3D scaffold hopping with competitive bioactivities to meet an important clinical need

Discovery of Diverse Human Dihydroorotate Dehydrogenase Inhibitors as Immunosuppressive Agents by Structure-Based Virtual Screening

This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (<i>h</i>DHODH) inhibitors. Eighteen compounds with IC₅₀ values ranging from 0.11 to 18.8 μM were identified as novel <i>h</i>DHODH inhibitors that exhibited overall species-selectivity over <i>Plasmodium falciparum</i> dihydroorotate dehydrogenase (<i>pf</i>DHODH). Compound <b>8</b>, the most potent one, showed low micromolar inhibitory activity against <i>h</i>DHODH with an IC₅₀ value of 0.11 μM. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound <b>18</b> exhibited potent B-cell inhibitory activity (IC₅₀ = 1.78 μM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively

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Design, Synthesis, and Biological Evaluation of Pyrimido[4,5‑<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido­[4,5-<i>d</i>]­pyrimidine-2,4­(1<i>H</i>,3<i>H</i>)-dione derivatives were designed and synthesized, among which the most potent compound <b>20g</b> not only demonstrated significant inhibitory activity and selectivity for EGFR^L858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that <b>20g</b> might be used as a promising lead compound for further structural optimization as potent and selective EGFR^L858R/T790M inhibitors

Design, Synthesis, and Biological Evaluation of Pyrimido[4,5‑<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido­[4,5-<i>d</i>]­pyrimidine-2,4­(1<i>H</i>,3<i>H</i>)-dione derivatives were designed and synthesized, among which the most potent compound <b>20g</b> not only demonstrated significant inhibitory activity and selectivity for EGFR^L858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that <b>20g</b> might be used as a promising lead compound for further structural optimization as potent and selective EGFR^L858R/T790M inhibitors

Design, Synthesis, and Biological Evaluation of Pyrimido[4,5‑<i>d</i>]pyrimidine-2,4(1<i>H</i>,3<i>H</i>)‑diones as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

First-generation epidermal growth factor receptor (EGFR) inhibitors, gefitinib and erlotinib, have achieved initially marked clinical efficacy for nonsmall cell lung cancer (NSCLC) patients with EGFR activating mutations. However, their clinical benefit was limited by the emergence of acquired resistance mutations. In most cases (approximately 60%), the resistance was caused by the secondary EGFR T790M gatekeeper mutation. Thus, it is still desirable to develop novel third-generation EGFR inhibitors to overcome T790M mutation while sparing wild-type (WT) EGFR. Herein, a series of pyrimido­[4,5-<i>d</i>]­pyrimidine-2,4­(1<i>H</i>,3<i>H</i>)-dione derivatives were designed and synthesized, among which the most potent compound <b>20g</b> not only demonstrated significant inhibitory activity and selectivity for EGFR^L858R/T790M and H1975 cells in vitro but also displayed outstanding antitumor efficiency in H1975 xenograft mouse model. The encouraging mutant-selective results at both in vitro and in vivo levels suggested that <b>20g</b> might be used as a promising lead compound for further structural optimization as potent and selective EGFR^L858R/T790M inhibitors

Discovery and Structural Optimization of N5-Substituted 6,7-Dioxo-6,7-dihydropteridines as Potent and Selective Epidermal Growth Factor Receptor (EGFR) Inhibitors against L858R/T790M Resistance Mutation

EGFR-targeted inhibitors (gefitinib and erlotinib) provided an effective strategy for the treatment of non-small-cell lung cancer. However, the EGFR T790M secondary mutation has become a leading cause of clinically acquired resistance to these agents. Herein, on the basis of the previously reported irreversible EGFR inhibitor (compound <b>9</b>), we present a structure-based design approach, which is rationalized via analyzing its binding model and comparing the differences of gatekeeper pocket between the T790M mutant and wild-type (WT) EGFR kinases. Guided by these results, a novel 6,7-dioxo-6,7-dihydropteridine scaffold was discovered and hydrophobic modifications at N5-position were conducted to strengthen nonpolar contacts and improve mutant selectivity over EGFR^WT. Finally, the most representative compound <b>17d</b> was identified. This work demonstrates the power of structure-based strategy in discovering lead compounds and provides molecular insights into the selectivity of EGFR^L858R/T790M over EGFR^WT, which may play an important role in designing new classes of mutant-selective EGFR inhibitors

Design, Synthesis, X‑ray Crystallographic Analysis, and Biological Evaluation of Thiazole Derivatives as Potent and Selective Inhibitors of Human Dihydroorotate Dehydrogenase

Human dihydroorotate dehydrogenase (<i>Hs</i>DHODH) is a flavin-dependent mitochondrial enzyme that has been certified as a potential therapeutic target for the treatment of rheumatoid arthritis and other autoimmune diseases. On the basis of lead compound <b>4</b>, which was previously identified as potential <i>Hs</i>DHODH inhibitor, a novel series of thiazole derivatives were designed and synthesized. The X-ray complex structures of the promising analogues <b>12</b> and <b>33</b> confirmed that these inhibitors bind at the putative ubiquinone binding tunnel and guided us to explore more potent inhibitors, such as compounds <b>44</b>, <b>46</b>, and <b>47</b> which showed double digit nanomolar activities of 26, 18, and 29 nM, respectively. Moreover, <b>44</b> presented considerable anti-inflammation effect in vivo and significantly alleviated foot swelling in a dose-dependent manner, which disclosed that thiazole-scaffold analogues can be developed into the drug candidates for the treatment of rheumatoid arthritis by suppressing the bioactivity of <i>Hs</i>DHODH

Discovery and Rational Design of Natural-Product-Derived 2‑Phenyl-3,4-dihydro‑2<i>H</i>‑benzo[<i>f</i>]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes

Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2<i>H</i>-benzo­[<i>f</i>]­chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds <b>22a</b> and <b>24a</b> are the most potent ones (IC₅₀ ≈ 2.0 nM) with good pharmacokinetic profiles. Compound <b>22a</b> demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of <b>22a</b> in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented