bibw-2992 and Lung-Neoplasms

Covalent drugs have made a major impact on human health but until recently were shunned by the pharmaceutical industry over concerns about the potential for toxicity. A resurgence has occurred driven by the clinical success of targeted covalent inhibitors (TCIs), with eight drugs approved over the past decade. The opportunity to create unique drugs by exploiting the covalent mechanism of action has enabled clinically decisive target product profiles to be achieved. TCIs have revolutionized the treatment paradigm for non-small-cell lung cancer and chronic lymphocytic leukemia. This Perspective will highlight the clinical and financial success of this class of drugs and provide early insight into toxicity, a key factor that had hindered progress in the field. Further innovation in the TCI approach, including expanding beyond cysteine-directed electrophiles, kinases, and cancer, highlights the broad opportunity to deliver a new generation of breakthrough therapies.

Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Phosphotransferases; Protein Kinase Inhibitors

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 1

Topics: Animals; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Mice; Mutagenesis, Insertional; Mutation; Protein Kinase Inhibitors

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Diamines; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Lung Neoplasms; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 1; Structure-Activity Relationship

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Catalytic Domain; Cell Line, Tumor; Cell Proliferation; Drug Screening Assays, Antitumor; Histone Deacetylase 6; Histone Deacetylase Inhibitors; HSP90 Heat-Shock Proteins; Humans; Hydroxamic Acids; Isoindoles; Lung Neoplasms; Male; Mice, Inbred BALB C; Molecular Docking Simulation; Protein Binding; Xenograft Model Antitumor Assays

Studies on the third-generation of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) targeting EGFR

Topics: Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Cell Survival; Cells, Cultured; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Lung Neoplasms; Molecular Conformation; Molecular Docking Simulation; Protein Kinase Inhibitors; Pyrimidines; Structure-Activity Relationship

Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine

Topics: Animals; Antineoplastic Agents; Binding Sites; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Drug Resistance, Neoplasm; ErbB Receptors; Exons; Humans; Lung Neoplasms; Male; Mice, Inbred ICR; Mice, Nude; Mutation; Protein Kinase Inhibitors; Pyrimidines; Rats; Receptor, ErbB-2; Structure-Activity Relationship; Xenograft Model Antitumor Assays

Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Gefitinib; Humans; Imidazoles; Lung Neoplasms; Molecular Docking Simulation; Point Mutation; Protein Kinase Inhibitors; Quinazolines; Structure-Activity Relationship

Reversible epidermal growth factor receptor (EGFR) inhibitors prompt a beneficial clinical response in non-small cell lung cancer patients who harbor activating mutations in EGFR. However, resistance mutations, particularly the gatekeeper mutation T790M, limit this efficacy. Here, we describe a structure-guided development of a series of covalent and mutant-selective EGFR inhibitors that effectively target the T790M mutant. The pyrazolopyrimidine-based core differs structurally from that of aminopyrimidine-based third-generation EGFR inhibitors and therefore constitutes a new set of inhibitors that target this mechanism of drug resistance. These inhibitors exhibited strong inhibitory effects toward EGFR kinase activity and excellent inhibition of cell growth in the drug-resistant cell line H1975, without significantly affecting EGFR wild-type cell lines. Additionally, we present the in vitro ADME/DMPK parameters for a subset of the inhibitors as well as in vivo pharmacokinetics in mice for a candidate with promising activity profile.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Humans; Lung Neoplasms; Male; Mice; Molecular Docking Simulation; Point Mutation; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

Because of the development of drug-resistance mutations, particularly the "gatekeeper" threonine(790)-to-methionine(790) (T790M) mutation in the ATP-binding pocket of the epidermal growth factor receptor (EGFR), the current generation of EGFR tyrosine kinase inhibitors lost their clinical efficacy. Recently, a large number of small-molecule inhibitors with striking inhibitory potency against EGFR mutants with the T790M change have been identified. In particular, the inhibitors rociletinib and osimertinib, which can selectively target both sensitizing mutations and the T790M resistance while sparing the wild-type (WT) form of the receptor, have been designated as breakthrough therapies in the treatment of mutant non-small-cell lung cancer (NSCLC) by the U.S. FDA in 2014. We hope that this review on the small-molecule EGFR T790M inhibitors, along with their discovery strategies, will assist in the design of future T790M-containing EGFR inhibitors with high levels of selectivity over WT EGFR, broad kinase selectivity, and desirable physicochemical properties.

Topics: Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Lung Neoplasms; Mice; Models, Molecular; Molecular Structure; Neoplasms, Experimental; Protein Kinase Inhibitors; Pyridones; Small Molecule Libraries; Structure-Activity Relationship

Over the past decade, first and second generation EGFR inhibitors have significantly improved outcomes for lung cancer patients with activating mutations in EGFR. However, both resistance through a secondary T790M mutation at the gatekeeper residue and dose-limiting toxicities from wild-type (WT) EGFR inhibition ultimately limit the full potential of these therapies to control mutant EGFR-driven tumors and new therapies are urgently needed. Herein, we describe our approach toward the discovery of 47 (EGF816, nazartinib), a novel, covalent mutant-selective EGFR inhibitor with equipotent activity on both oncogenic and T790M-resistant EGFR mutations. Through molecular docking studies we converted a mutant-selective high-throughput screening hit (7) into a number of targeted covalent EGFR inhibitors with equipotent activity across mutants EGFR and good WT-EGFR selectivity. We used an abbreviated in vivo efficacy study for prioritizing compounds with good tolerability and efficacy that ultimately led to the selection of 47 as the clinical candidate.

Topics: Animals; Antineoplastic Agents; Benzimidazoles; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Models, Molecular; Molecular Conformation; Mutation; Neoplasms, Experimental; Nicotine; Protein Kinase Inhibitors; Rats; Rats, Wistar; Structure-Activity Relationship

Epidermal growth factor receptor (EGFR) inhibitors have been used clinically in the treatment of non-small-cell lung cancer (NSCLC) patients harboring sensitizing (or activating) mutations for a number of years. Despite encouraging clinical efficacy with these agents, in many patients resistance develops leading to disease progression. In most cases, this resistance is in the form of the T790M mutation. In addition, EGFR wild type receptor inhibition inherent with these agents can lead to dose limiting toxicities of rash and diarrhea. We describe herein the evolution of an early, mutant selective lead to the clinical candidate AZD9291, an irreversible inhibitor of both EGFR sensitizing (EGFRm+) and T790M resistance mutations with selectivity over the wild type form of the receptor. Following observations of significant tumor inhibition in preclinical models, the clinical candidate was administered clinically to patients with T790M positive EGFR-TKI resistant NSCLC and early efficacy has been observed, accompanied by an encouraging safety profile.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Chemistry Techniques, Synthetic; Drug Resistance, Neoplasm; ErbB Receptors; Female; Humans; Inhibitory Concentration 50; Lung Neoplasms; Male; Mice; Middle Aged; Mutation; Protein Kinase Inhibitors; Rats, Inbred Strains; Xenograft Model Antitumor Assays

Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Drug Resistance, Neoplasm; ErbB Receptors; Ether-A-Go-Go Potassium Channels; Humans; Lung Neoplasms; Mice, Inbred BALB C; Protein Kinase Inhibitors; Xenograft Model Antitumor Assays

A focused library of furanopyrimidine (350 compounds) was rapidly synthesized in parallel reactors and in situ screened for Aurora and epidermal growth factor receptor (EGFR) kinase activity, leading to the identification of some interesting hits. On the basis of structural biology observations, the hit 1a was modified to better fit the back pocket, producing the potent Aurora inhibitor 3 with submicromolar antiproliferative activity in HCT-116 colon cancer cell line. On the basis of docking studies with EGFR hit 1s, introduction of acrylamide Michael acceptor group led to 8, which inhibited both the wild and mutant EGFR kinase and also showed antiproliferative activity in HCC827 lung cancer cell line. Furthermore, the X-ray cocrystal study of 3 and 8 in complex with Aurora and EGFR, respectively, confirmed their hypothesized binding modes. Library construction, in situ screening, and structure-based drug design (SBDD) strategy described here could be applied for the lead identification of other kinases.

Topics: Antineoplastic Agents; Aurora Kinases; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Crystallography, X-Ray; ErbB Receptors; Furans; Humans; Inhibitory Concentration 50; Lung Neoplasms; Magnetic Resonance Spectroscopy; Models, Molecular; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Pyrimidines; Spectrometry, Mass, Fast Atom Bombardment

Genetic alterations in the kinase domain of the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) patients are associated with sensitivity to treatment with small molecule tyrosine kinase inhibitors. Although first-generation reversible, ATP-competitive inhibitors showed encouraging clinical responses in lung adenocarcinoma tumors harboring such EGFR mutations, almost all patients developed resistance to these inhibitors over time. Such resistance to first-generation EGFR inhibitors was frequently linked to an acquired T790M point mutation in the kinase domain of EGFR, or upregulation of signaling pathways downstream of HER3. Overcoming these mechanisms of resistance, as well as primary resistance to reversible EGFR inhibitors driven by a subset of EGFR mutations, will be necessary for development of an effective targeted therapy regimen. Here, we show that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFR and HER2 mutants, including erlotinib-resistant isoforms. Consistent with this activity, BIBW2992 suppresses transformation in isogenic cell-based assays, inhibits survival of cancer cell lines and induces tumor regression in xenograft and transgenic lung cancer models, with superior activity over erlotinib. These findings encourage further testing of BIBW2992 in lung cancer patients harboring EGFR or HER2 oncogenes.

Topics: Afatinib; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Survival; Disease Models, Animal; ErbB Receptors; Female; Humans; Lung Neoplasms; Mice; Mice, Nude; Mice, Transgenic; NIH 3T3 Cells; Phosphorylation; Quinazolines; Receptor, ErbB-2; Treatment Outcome; Tumor Cells, Cultured; Xenograft Model Antitumor Assays