Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

To investigate large library docking’s ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field

Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

To investigate large library docking’s ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field

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

Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

To investigate large library docking’s ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field

Selectivity Challenges in Docking Screens for GPCR Targets and Antitargets

To investigate large library docking’s ability to find molecules with joint activity against on-targets and selectivity versus antitargets, the dopamine D₂ and serotonin 5-HT_2A receptors were targeted, seeking selectivity against the histamine H₁ receptor. In a second campaign, κ-opioid receptor ligands were sought with selectivity versus the μ-opioid receptor. While hit rates ranged from 40% to 63% against the on-targets, they were just as good against the antitargets, even though the molecules were selected for their putative lack of binding to the off-targets. Affinities, too, were often as good or better for the off-targets. Even though it was occasionally possible to find selective molecules, such as a mid-nanomolar D₂/5-HT_2A ligand with 21-fold selectivity versus the H₁ receptor, this was the exception. Whereas false-negatives are tolerable in docking screens against on-targets, they are intolerable against antitargets; addressing this problem may demand new strategies in the field

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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