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1.
J Med Chem ; 67(14): 11701-11711, 2024 Jul 25.
Article in English | MEDLINE | ID: mdl-39009041

ABSTRACT

Identifying promising chemical starting points for small molecule inhibitors of active, GTP-loaded KRAS "on" remains of great importance to clinical oncology and represents a significant challenge in medicinal chemistry. Here, we describe broadly applicable learnings from a KRAS hit finding campaign: While we initially identified KRAS inhibitors in a biochemical high-throughput screen, we later discovered that compound potencies were all but assay artifacts linked to metal salts interfering with KRAS AlphaScreen assay technology. The source of the apparent biochemical KRAS inhibition was ultimately traced to unavoidable palladium impurities from chemical synthesis. This discovery led to the development of a Metal Ion Interference Set (MIIS) for up-front assay development and testing. Profiling of the MIIS across 74 assays revealed a reduced interference liability of label-free biophysical assays and, as a result, provided general estimates for luminescence- and fluorescence-based assay susceptibility to metal salt interference.


Subject(s)
Palladium , Proto-Oncogene Proteins p21(ras) , Humans , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/genetics , Proto-Oncogene Proteins p21(ras)/metabolism , Palladium/chemistry , High-Throughput Screening Assays/methods , Salts/chemistry
2.
Nat Cancer ; 3(7): 821-836, 2022 07.
Article in English | MEDLINE | ID: mdl-35883003

ABSTRACT

Oncogenic alterations in human epidermal growth factor receptor 2 (HER2) occur in approximately 2% of patients with non-small cell lung cancer and predominantly affect the tyrosine kinase domain and cluster in exon 20 of the ERBB2 gene. Most clinical-grade tyrosine kinase inhibitors are limited by either insufficient selectivity against wild-type (WT) epidermal growth factor receptor (EGFR), which is a major cause of dose-limiting toxicity or by potency against HER2 exon 20 mutant variants. Here we report the discovery of covalent tyrosine kinase inhibitors that potently inhibit HER2 exon 20 mutants while sparing WT EGFR, which reduce tumor cell survival and proliferation in vitro and result in regressions in preclinical xenograft models of HER2 exon 20 mutant non-small cell lung cancer, concomitant with inhibition of downstream HER2 signaling. Our results suggest that HER2 exon 20 insertion-driven tumors can be effectively treated by a potent and highly selective HER2 inhibitor while sparing WT EGFR, paving the way for clinical translation.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Carcinoma, Non-Small-Cell Lung/drug therapy , ErbB Receptors/genetics , Exons/genetics , Genes, erbB-2 , Humans , Lung Neoplasms/drug therapy , Protein Kinase Inhibitors/pharmacology , Receptor, ErbB-2/genetics
4.
J Med Chem ; 64(10): 6569-6580, 2021 05 27.
Article in English | MEDLINE | ID: mdl-33719426

ABSTRACT

KRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS and SOS1, crucial for the activation of KRAS, is a typical, challenging PPI with a large contact surface area and high affinity. Here, we report that the addition of only one atom placed between Y884SOS1 and A73KRAS is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of BI-3406. Combination with the upstream EGFR inhibitor afatinib shows in vivo efficacy against KRASG13D mutant colorectal tumor cells, demonstrating the utility of BI-3406 to probe SOS1 biology. These findings challenge the dogma that large molecules are required to disrupt challenging PPIs. Instead, a "foot in the door" approach, whereby single atoms or small functional groups placed between key PPI interactions, can lead to potent inhibitors even for challenging PPIs such as SOS1-KRAS.


Subject(s)
Proto-Oncogene Proteins p21(ras)/metabolism , SOS1 Protein/metabolism , Afatinib/chemistry , Afatinib/metabolism , Afatinib/therapeutic use , Allosteric Regulation/drug effects , Binding Sites , Catalytic Domain , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/pathology , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Humans , Molecular Dynamics Simulation , Mutagenesis, Site-Directed , Protein Interaction Maps/drug effects , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/genetics , Quinazolines/chemistry , Quinazolines/metabolism , Quinazolines/pharmacology , Quinazolines/therapeutic use , SOS1 Protein/agonists , SOS1 Protein/antagonists & inhibitors , SOS1 Protein/genetics
5.
Int J Mol Sci ; 22(2)2021 Jan 08.
Article in English | MEDLINE | ID: mdl-33429995

ABSTRACT

We describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens.


Subject(s)
Drug Discovery , Protein Kinase Inhibitors/chemistry , Protein Serine-Threonine Kinases/chemistry , Small Molecule Libraries/chemistry , Humans , Protein Kinase Inhibitors/therapeutic use , Protein Serine-Threonine Kinases/antagonists & inhibitors , Small Molecule Libraries/therapeutic use , Structure-Activity Relationship
6.
Blood ; 137(15): 2070-2084, 2021 04 15.
Article in English | MEDLINE | ID: mdl-33512435

ABSTRACT

The KIT D816V mutation is found in >80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs. Therefore, KIT D816V represents a prime therapeutic target for SM. Here, we generated a panel of patient-specific KIT D816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM and mast cell leukemia to develop a patient-specific SM disease model for mechanistic and drug-discovery studies. KIT D816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineered KIT D816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed for KIT D816V iPSC hematopoiesis. KIT D816V causes constitutive activation of the KIT tyrosine kinase receptor, and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib, a US Food and Drug Administration-approved angiokinase inhibitor that targets vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derived KIT D816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the adenosine triphosphate binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V-targeted therapy of advanced SM.


Subject(s)
Antineoplastic Agents/pharmacology , Indoles/pharmacology , Mastocytosis, Systemic/drug therapy , Point Mutation/drug effects , Proto-Oncogene Proteins c-kit/genetics , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Induced Pluripotent Stem Cells/pathology , Mastocytosis, Systemic/genetics , Mastocytosis, Systemic/pathology , Tumor Cells, Cultured
7.
Cancer Discov ; 11(1): 142-157, 2021 01.
Article in English | MEDLINE | ID: mdl-32816843

ABSTRACT

KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective, and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors. SIGNIFICANCE: To date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS-mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins, G12D, G12V, G12C, and G13D.See related commentary by Zhao et al., p. 17.This article is highlighted in the In This Issue feature, p. 1.


Subject(s)
Lung Neoplasms , Proto-Oncogene Proteins p21(ras) , Cell Line, Tumor , Humans , Mitogen-Activated Protein Kinase Kinases , Mutation , Nucleotides , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins p21(ras)/genetics
8.
ACS Cent Sci ; 6(7): 1223-1230, 2020 Jul 22.
Article in English | MEDLINE | ID: mdl-32724856

ABSTRACT

Protein degraders, also known as proteolysis targeting chimeras (PROTACs), are bifunctional small molecules that promote cellular degradation of a protein of interest (POI). PROTACs act as molecular mediators, bringing an E3 ligase and a POI into proximity, thus promoting ubiquitination and degradation of the targeted POI. Despite their great promise as next-generation pharmaceutical drugs, the development of new PROTACs is challenged by the complexity of the system, which involves binary and ternary interactions between components. Here, we demonstrate the strength of native mass spectrometry (nMS), a label-free technique, to provide novel insight into PROTAC-mediated protein interactions. We show that nMS can monitor the formation of ternary E3-PROTAC-POI complexes and detect various intermediate species in a single experiment. A unique benefit of the method is its ability to reveal preferentially formed E3-PROTAC-POI combinations in competition experiments with multiple substrate proteins, thereby positioning it as an ideal high-throughput screening strategy during the development of new PROTACs.

9.
Mol Cancer Ther ; 19(4): 1018-1030, 2020 04.
Article in English | MEDLINE | ID: mdl-32024684

ABSTRACT

Natural killer (NK) cells play a pivotal role in controlling cancer. Multiple extracellular receptors and internal signaling nodes tightly regulate NK activation. Cyclin-dependent kinases of the mediator complex (CDK8 and CDK19) were described as a signaling intermediates in NK cells. Here, we report for the first time the development and use of CDK8/19 inhibitors to suppress phosphorylation of STAT1S727 in NK cells and to augment the production of the cytolytic molecules perforin and granzyme B (GZMB). Functionally, this resulted in enhanced NK-cell-mediated lysis of primary leukemia cells. Treatment with the CDK8/19 inhibitor BI-1347 increased the response rate and survival of mice bearing melanoma and breast cancer xenografts. In addition, CDK8/19 inhibition augmented the antitumoral activity of anti-PD-1 antibody and SMAC mimetic therapy, both agents that promote T-cell-mediated antitumor immunity. Treatment with the SMAC mimetic compound BI-8382 resulted in an increased number of NK cells infiltrating EMT6 tumors. Combination of the CDK8/19 inhibitor BI-1347, which augments the amount of degranulation enzymes, with the SMAC mimetic BI-8382 resulted in increased survival of mice carrying the EMT6 breast cancer model. The observed survival benefit was dependent on an intermittent treatment schedule of BI-1347, suggesting the importance of circumventing a hyporesponsive state of NK cells. These results suggest that CDK8/19 inhibitors can be combined with modulators of the adaptive immune system to inhibit the growth of solid tumors, independent of their activity on cancer cells, but rather through promoting NK-cell function.


Subject(s)
Breast Neoplasms/drug therapy , Cyclin-Dependent Kinase 8/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Killer Cells, Natural/immunology , Leukemia, Myeloid, Acute/drug therapy , Melanoma, Experimental/drug therapy , Protein Kinase Inhibitors/pharmacology , Animals , Apoptosis , Breast Neoplasms/enzymology , Breast Neoplasms/immunology , Breast Neoplasms/pathology , Cell Proliferation , Cytotoxicity, Immunologic/immunology , Female , Humans , Killer Cells, Natural/drug effects , Leukemia, Myeloid, Acute/enzymology , Leukemia, Myeloid, Acute/immunology , Leukemia, Myeloid, Acute/pathology , Melanoma, Experimental/enzymology , Melanoma, Experimental/immunology , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, SCID , Phosphorylation , STAT1 Transcription Factor/metabolism , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
10.
J Med Chem ; 62(22): 10272-10293, 2019 11 27.
Article in English | MEDLINE | ID: mdl-31689114

ABSTRACT

The epidermal growth factor receptor (EGFR), when carrying an activating mutation like del19 or L858R, acts as an oncogenic driver in a subset of lung tumors. While tumor responses to tyrosine kinase inhibitors (TKIs) are accompanied by marked tumor shrinkage, the response is usually not durable. Most patients relapse within two years of therapy often due to acquisition of an additional mutation in EGFR kinase domain that confers resistance to TKIs. Crucially, oncogenic EGFR harboring both resistance mutations, T790M and C797S, can no longer be inhibited by currently approved EGFR TKIs. Here, we describe the discovery of BI-4020, which is a noncovalent, wild-type EGFR sparing, macrocyclic TKI. BI-4020 potently inhibits the above-described EGFR variants and induces tumor regressions in a cross-resistant EGFRdel19 T790M C797S xenograft model. Key was the identification of a highly selective but moderately potent benzimidazole followed by complete rigidification of the molecule through macrocyclization.


Subject(s)
Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Animals , Antineoplastic Agents/pharmacokinetics , Benzimidazoles/chemistry , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Crystallography, X-Ray , Cyclization , Entropy , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/chemistry , ErbB Receptors/genetics , Female , Hepatocytes , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mice, Transgenic , Mutation , Protein Conformation , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Xenograft Model Antitumor Assays
11.
J Med Chem ; 62(17): 7976-7997, 2019 09 12.
Article in English | MEDLINE | ID: mdl-31365252

ABSTRACT

Phosphoglycerate dehydrogenase (PHGDH) is known to be the rate-limiting enzyme in the serine synthesis pathway in humans. It converts glycolysis-derived 3-phosphoglycerate to 3-phosphopyruvate in a co-factor-dependent oxidation reaction. Herein, we report the discovery of BI-4916, a prodrug of the co-factor nicotinamide adenine dinucleotide (NADH/NAD+)-competitive PHGDH inhibitor BI-4924, which has shown high selectivity against the majority of other dehydrogenase targets. Starting with a fragment-based screening, a subsequent hit optimization using structure-based drug design was conducted to deliver a single-digit nanomolar lead series and to improve potency by 6 orders of magnitude. To this end, an intracellular ester cleavage mechanism of the ester prodrug was utilized to achieve intracellular enrichment of the actual carboxylic acid based drug and thus overcome high cytosolic levels of the competitive cofactors NADH/NAD+.


Subject(s)
Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Phosphoglycerate Dehydrogenase/antagonists & inhibitors , Serine/antagonists & inhibitors , Cell Line, Tumor , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Phosphoglycerate Dehydrogenase/metabolism , Serine/biosynthesis , Structure-Activity Relationship
12.
Nat Chem Biol ; 15(8): 846, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31267096

ABSTRACT

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read "The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis12,13." The affected text of the right column should read "SMARCA2/4BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel-Lindau (VHL) or cereblon5,6,10,11,25,26,27." The errors have been corrected in the PDF version of the paper.

13.
Nat Chem Biol ; 15(7): 672-680, 2019 07.
Article in English | MEDLINE | ID: mdl-31178587

ABSTRACT

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.


Subject(s)
Chromatin Assembly and Disassembly/genetics , DNA-Binding Proteins/genetics , Leukemia, Myeloid, Acute/genetics , Nuclear Proteins/genetics , Cell Proliferation , Cells, Cultured , DNA-Binding Proteins/metabolism , Humans , Leukemia, Myeloid, Acute/metabolism , Molecular Structure , Nuclear Proteins/metabolism
14.
J Med Chem ; 62(5): 2508-2520, 2019 03 14.
Article in English | MEDLINE | ID: mdl-30739444

ABSTRACT

Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.


Subject(s)
Focal Adhesion Kinase 1/drug effects , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Recombinant Proteins/metabolism , Cell Line, Tumor , Cell Proliferation , Focal Adhesion Kinase 1/genetics , Focal Adhesion Kinase 1/metabolism , Humans , Ligands , Proteolysis , RNA Interference
15.
Cell Rep ; 20(12): 2860-2875, 2017 Sep 19.
Article in English | MEDLINE | ID: mdl-28930682

ABSTRACT

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics.


Subject(s)
Proteolysis , Proto-Oncogene Proteins c-bcl-6/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , DNA/metabolism , Gene Expression Regulation, Neoplastic/drug effects , HEK293 Cells , Humans , Inhibitory Concentration 50 , Kinetics , Models, Molecular , Proteasome Endopeptidase Complex/metabolism , Protein Binding/drug effects , Protein Domains , Proteolysis/drug effects , Proto-Oncogene Proteins c-bcl-6/antagonists & inhibitors , Proto-Oncogene Proteins c-bcl-6/chemistry , Pyrimidines/pharmacology , Structure-Activity Relationship , Ubiquitination/drug effects
16.
PLoS One ; 12(8): e0181585, 2017.
Article in English | MEDLINE | ID: mdl-28767711

ABSTRACT

Protein kinases are highly tractable targets for drug discovery. However, the biological function and therapeutic potential of the majority of the 500+ human protein kinases remains unknown. We have developed physical and virtual collections of small molecule inhibitors, which we call chemogenomic sets, that are designed to inhibit the catalytic function of almost half the human protein kinases. In this manuscript we share our progress towards generation of a comprehensive kinase chemogenomic set (KCGS), release kinome profiling data of a large inhibitor set (Published Kinase Inhibitor Set 2 (PKIS2)), and outline a process through which the community can openly collaborate to create a KCGS that probes the full complement of human protein kinases.


Subject(s)
Databases, Pharmaceutical , Protein Kinase Inhibitors/pharmacology , Small Molecule Libraries/pharmacology , Drug Discovery/methods , Genomics/methods , Humans , Protein Kinase Inhibitors/chemistry , Small Molecule Libraries/chemistry , Structure-Activity Relationship
17.
J Med Chem ; 59(22): 10147-10162, 2016 11 23.
Article in English | MEDLINE | ID: mdl-27775892

ABSTRACT

Scaffold modification based on Wang's pioneering MDM2-p53 inhibitors led to novel, chemically stable spiro-oxindole compounds bearing a spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one scaffold that are not prone to epimerization as observed for the initial spiro[3H-indole-3,3'-pyrrolidin]-2(1H)-one scaffold. Further structure-based optimization inspired by natural product architectures led to a complex fused ring system ideally suited to bind to the MDM2 protein and to interrupt its protein-protein interaction (PPI) with TP53. The compounds are highly selective and show in vivo efficacy in a SJSA-1 xenograft model even when given as a single dose as demonstrated for 4-[(3S,3'S,3'aS,5'R,6'aS)-6-chloro-3'-(3-chloro-2-fluorophenyl)-1'-(cyclopropylmethyl)-2-oxo-1,2,3',3'a,4',5',6',6'a-octahydro-1'H-spiro[indole-3,2'-pyrrolo[3,2-b]pyrrole]-5'-yl]benzoic acid (BI-0252).


Subject(s)
Drug Discovery , Indoles/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Pyrrolidinones/pharmacology , Spiro Compounds/pharmacology , Tumor Suppressor Protein p53/antagonists & inhibitors , Administration, Oral , Dose-Response Relationship, Drug , Humans , Indoles/administration & dosage , Indoles/chemistry , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-mdm2/metabolism , Pyrrolidinones/administration & dosage , Pyrrolidinones/chemistry , Spiro Compounds/administration & dosage , Spiro Compounds/chemistry , Structure-Activity Relationship , Tumor Suppressor Protein p53/metabolism
18.
Mol Inform ; 29(3): 233-42, 2010 Mar 15.
Article in English | MEDLINE | ID: mdl-27462766

ABSTRACT

Within the last decades, the detailed knowledge on the impact of membrane bound drug efflux transporters of the ATP binding cassette (ABC) protein family on the pharmacological profile of drugs has enormously increased. Especially, ABCB1 (P-glycoprotein, P-gp, MDR1) has attracted particular interest in medicinal chemistry, since it determines the clinical efficacy, side effects and toxicity risks of drug candidates. Based on this, the development of in silico models that provide rapid and cost-effective screening tools for the classification of substrates and nonsubstrates of ABCB1 is an urgent need in contemporary ADMET profiling. A characteristic hallmark feature of this transporter is its polyspecific ligand recognition pattern. In this study we describe a method for classifying ABCB1 ligands in terms of simple, conjunctive rules (RuleFit) based on interpretable ADMET features. The retrieved results showed that models based on large, very diverse data sets gave better classification performance than models based on smaller, more homogenous training sets. The best model achieved gave a correct classification rate of 0.90 for an external validation set. Furthermore, from the interpretation of the best performing model it could be concluded that in comparison to nonsubstrates ABCB1 substrates generally show a higher number of hydrogen-bond acceptors, are more flexible and exhibit higher logP values.

19.
Chem Biodivers ; 6(11): 1960-9, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19937827

ABSTRACT

ABC-type drug efflux pumps, e.g., ABCB1 (=P-glycoprotein, =MDR1), ABCC1 (=MRP1), and ABCG2 (=MXR, =BCRP), confer a multi-drug resistance (MDR) phenotype to cancer cells. Furthermore, the important contribution of ABC transporters for bioavailability, distribution, elimination, and blood-brain barrier permeation of drug candidates is increasingly recognized. This review presents an overview on the different computational methods and models pursued to predict ABC transporter substrate properties of drug-like compounds. They encompass ligand-based approaches ranging from 'simple rule'-based efforts to sophisticated machine learning methods. Many of these models show excellent performance for the data sets used. However, due to the complex nature of the applied methods, useful interpretation of the models that can be directly translated into chemical structures by the medicinal chemist is rather difficult. Additionally, very recent and promising attempts in the field of structure-based modeling of ABC transporters, which embody homology modeling as well as recently published X-ray structures of murine ABCB1, will be discussed.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Drug-Related Side Effects and Adverse Reactions , Pharmaceutical Preparations/metabolism , Absorption , Animals , Computer Simulation , Forecasting , Humans , Ligands , Models, Biological , Models, Molecular , Pharmacokinetics , Structure-Activity Relationship , Tissue Distribution
20.
Am J Respir Crit Care Med ; 173(6): 599-606, 2006 Mar 15.
Article in English | MEDLINE | ID: mdl-16387807

ABSTRACT

RATIONALE AND OBJECTIVE: During allergic lung inflammation dendritic cells (DCs) direct the generation and function of effector T-helper type 2 cells. T-helper type 2 cells not only orchestrate the inflammatory processes in the tissue by inducing the accumulation and activation of proinflammatory cells but also induce IgE production by B cells. Thus, inhibitors of DC function should have therapeutic benefits in patients with allergies. METHODS AND MEASUREMENTS: VAF347, a novel low molecular weight immunomodulator, is described and acts as an antiinflammatory compound by a dual mode of action. RESULTS: VAF347 inhibited the function of human monocyte-derived DCs to induce T-cell proliferation and cytokine production. Mechanistically, this effect may be due to reduced expression of CD86, HLA-DR, and interleukin 6 by DCs. In addition, the compound inhibited IgE synthesis in an isotype-specific fashion by human B lymphocytes. In a mouse model of antigen-induced eosinophilic inflammation, VAF347 blocked lung eosinophilia, mucus hyperplasia, and serum IgE levels, representing the hallmarks of allergic lung inflammation. The biological effects in vivo are most likely mediated by the immunoregulatory role of VAF347 on DCs because allergic lung inflammation was also inhibited in B-cell-deficient mice. CONCLUSION: VAF347 represents a novel type of immunomodulator by affecting two major pathways in allergic airway pathogenesis: dendritic cell-mediated T-helper-cell activation and induction of IgE production by human B lymphocytes.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , B-Lymphocytes/drug effects , Dendritic Cells/drug effects , Pyrimidines/pharmacology , Respiratory Hypersensitivity/prevention & control , Animals , B-Lymphocytes/immunology , B7-2 Antigen/metabolism , Cell Proliferation/drug effects , Dendritic Cells/immunology , Disease Models, Animal , HLA-DR Antigens/metabolism , Humans , Immunoglobulin E/biosynthesis , Immunoglobulin E/drug effects , In Vitro Techniques , Interleukin-6/metabolism , Lymphocyte Activation/drug effects , Mice , Mice, Inbred C57BL , Molecular Weight , Respiratory Hypersensitivity/immunology , Respiratory Hypersensitivity/pathology , Th2 Cells/drug effects , Th2 Cells/immunology , Th2 Cells/metabolism
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