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1.
J Med Chem ; 65(9): 6643-6655, 2022 05 12.
Article in English | MEDLINE | ID: mdl-35486541

ABSTRACT

Despite the clinical efficacy of epidermal growth factor receptor (EGFR) inhibitors, a subset of patients with non-small cell lung cancer displays insertion mutations in exon20 in EGFR and Her2 with limited treatment options. Here, we present the development and characterization of the novel covalent inhibitors LDC8201 and LDC0496 based on a 1H-pyrrolo[2,3-b]pyridine scaffold. They exhibited intense inhibitory potency toward EGFR and Her2 exon20 insertion mutations as well as selectivity over wild type EGFR and within the kinome. Complex crystal structures with the inhibitors and biochemical and cellular on-target activity document their favorable binding characteristics. Ultimately, we observed tumor shrinkage in mice engrafted with patient-derived EGFR-H773_V774insNPH mutant cells during treatment with LDC8201. Together, these results highlight the potential of covalent pyrrolopyridines as inhibitors to target exon20 insertion mutations.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Carcinoma, Non-Small-Cell Lung/drug therapy , Humans , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mice , Mutagenesis, Insertional , Mutation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use
2.
ChemMedChem ; 17(10): e202100776, 2022 05 18.
Article in English | MEDLINE | ID: mdl-35170857

ABSTRACT

Akt is a protein kinase that has been implicated in the progression of cancerous tumours. A number of covalent allosteric Akt inhibitors are known, and based on these scaffolds, a small library of novel potential covalent allosteric imidazopyridine-based inhibitors was designed. The envisaged compounds were synthesised, with click chemistry enabling a modular approach to a number of the target compounds. The binding modes, potencies and antiproliferative activities of these synthesised compounds were explored, thereby furthering the structure activity relationship knowledge of this class of Akt inhibitors. Three novel covalent inhibitors were identified, exhibiting moderate activity against Akt1 and various cancer cell lines, potentially paving the way for future covalent allosteric inhibitors with improved properties.


Subject(s)
Protein Kinase Inhibitors , Proto-Oncogene Proteins c-akt , Allosteric Regulation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Structure-Activity Relationship
3.
Nat Commun ; 12(1): 5297, 2021 09 06.
Article in English | MEDLINE | ID: mdl-34489430

ABSTRACT

The protein kinase Akt plays a pivotal role in cellular processes. However, its isoforms' distinct functions have not been resolved to date, mainly due to the lack of suitable biochemical and cellular tools. Against this background, we present the development of an isoform-dependent Ba/F3 model system to translate biochemical results on isoform specificity to the cellular level. Our cellular model system complemented by protein X-ray crystallography and structure-based ligand design results in covalent-allosteric Akt inhibitors with unique selectivity profiles. In a first proof-of-concept, the developed molecules allow studies on isoform-selective effects of Akt inhibition in cancer cells. Thus, this study will pave the way to resolve isoform-selective roles in health and disease and foster the development of next-generation therapeutics with superior on-target properties.


Subject(s)
Antineoplastic Agents/pharmacology , Lymphocytes/drug effects , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Small Molecule Libraries/pharmacology , Adaptor Proteins, Signal Transducing/genetics , Adaptor Proteins, Signal Transducing/metabolism , Allosteric Regulation , Allosteric Site , Animals , Antineoplastic Agents/chemical synthesis , Cell Line , Drug Design , Gene Expression , HEK293 Cells , Humans , Inhibitory Concentration 50 , Lymphocytes/cytology , Lymphocytes/enzymology , Mice , Mitogen-Activated Protein Kinase 1/genetics , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/genetics , Mitogen-Activated Protein Kinase 3/metabolism , Protein Kinase Inhibitors/chemical synthesis , Proto-Oncogene Proteins c-akt/chemistry , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Sf9 Cells , Small Molecule Libraries/chemical synthesis , Spodoptera , Structure-Activity Relationship
4.
ACS Med Chem Lett ; 11(3): 225-227, 2020 Mar 12.
Article in English | MEDLINE | ID: mdl-32184947

ABSTRACT

The protein kinase B (Akt) exemplifies an important switch of cell death and survival within the PI3K/Akt signaling pathway, which renders Akt a valuable target in diseases such as cancer. Herein, we give a short overview of clinical applications involving Akt, outline promising and innovative approaches to investigate the role of this kinase in diseases, and highlight the current challenges that require thorough investigation to set the groundwork for successful therapeutic strategies.

5.
Angew Chem Int Ed Engl ; 58(52): 18823-18829, 2019 12 19.
Article in English | MEDLINE | ID: mdl-31584233

ABSTRACT

Isoforms of protein kinase Akt are involved in essential processes including cell proliferation, survival, and metabolism. However, their individual roles in health and disease have not been thoroughly evaluated. Thus, there is an urgent need for perturbation studies, preferably mediated by highly selective bioactive small molecules. Herein, we present a structure-guided approach for the design of structurally diverse and pharmacologically beneficial covalent-allosteric modifiers, which enabled an investigation of the isoform-specific preferences and the important residues within the allosteric site of the different isoforms. The biochemical, cellular, and structural evaluations revealed interactions responsible for the selective binding profiles. The isoform-selective covalent-allosteric Akt inhibitors that emerged from this approach showed a conclusive structure-activity relationship and broke ground in the development of selective probes to delineate the isoform-specific functions of Akt kinases.


Subject(s)
Allosteric Regulation/physiology , Allosteric Site/physiology , Protein Isoforms/chemistry , Proto-Oncogene Proteins c-akt/metabolism , Humans , Structure-Activity Relationship
6.
Chem Sci ; 10(12): 3573-3585, 2019 Mar 28.
Article in English | MEDLINE | ID: mdl-30996949

ABSTRACT

The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation, cell growth, and apoptosis, rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

7.
Cancer Res ; 79(9): 2367-2378, 2019 05 01.
Article in English | MEDLINE | ID: mdl-30858154

ABSTRACT

Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. SIGNIFICANCE: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/dynamic optimization.


Subject(s)
Antineoplastic Agents/pharmacology , Colorectal Neoplasms/drug therapy , Mutation , Pancreatic Neoplasms/drug therapy , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/genetics , Pyridones/pharmacology , Pyrimidinones/pharmacology , Animals , Apoptosis , Cell Cycle , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , Drug Therapy, Combination , Female , Humans , Mice , Mice, Nude , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
8.
ChemMedChem ; 13(19): 2065-2072, 2018 10 08.
Article in English | MEDLINE | ID: mdl-30079978

ABSTRACT

The identification of compounds for dissecting biological functions and the development of novel drug molecules are central tasks that often require screening campaigns. However, the required architecture is cost- and time-intensive. Herein we describe the devices and technologies that comprise a Robotics-Assisted Screening Platform for Efficient Ligand Discovery (RASPELD), which we set up in an academic laboratory. RASPELD provides semi-automated high-end screening, and it can be maintained by graduate students. We demonstrate its successful application in biochemical and cellular screens for the identification and validation of bioactive chemical entities as candidate cancer-relevant inhibitors. Specifically, we examined the interaction between a transcription factor, Nrf2, and its key regulator, Keap1. We also examined drug-resistant mutants of the epidermal growth factor receptor (EGFR). Screening campaigns with more than 30 000 compounds were performed in a reasonable period of time. We identified the molecule RSL6586 as a starting point for hit optimization, which is currently ongoing.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Evaluation, Preclinical/methods , Robotics/methods , Small Molecule Libraries/pharmacology , Biological Assay , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/instrumentation , Education, Graduate , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/genetics , Humans , Kelch-Like ECH-Associated Protein 1/metabolism , Ligands , Mutation , NF-E2-Related Factor 2/metabolism , Protein Binding/drug effects , Protein Kinase Inhibitors/pharmacology , Robotics/instrumentation
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