Therapeutic advances of targeting receptor tyrosine kinases in cancer

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 14, 2024

Abstract Receptor tyrosine kinases (RTKs), a category of transmembrane receptors, have gained significant clinical attention in oncology due to their central role cancer pathogenesis. Genetic alterations, including mutations, amplifications, and overexpression certain RTKs, are critical creating environments conducive tumor development. Following discovery, extensive research has revealed how RTK dysregulation contributes oncogenesis, with many subtypes showing dependency on aberrant signaling for proliferation, survival progression. These findings paved the way targeted therapies that aim inhibit crucial biological pathways cancer. As result, RTKs emerged as primary targets anticancer therapeutic Over past two decades, this led synthesis validation numerous small molecule kinase inhibitors (TKIs), now effectively utilized treating various types. In manuscript we provide comprehensive understanding context We explored alterations specific receptors across different malignancies, special dedicated examination current inhibitors, highlighting potential therapies. By integrating latest evidence, seek elucidate pivotal biology efficacy inhibition promising treatment outcomes.

Language: Английский

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Understanding and Overcoming Resistance to Selective FGFR inhibitors Across FGFR2-Driven Malignancies

Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 30(21), P. 4943 - 4956

Published: Sept. 3, 2024

Abstract Purpose: Understanding resistance to selective FGFR inhibitors is crucial improve the clinical outcomes of patients with FGFR2-driven malignancies. Experimental Design: We analyzed sequential ctDNA, ± whole-exome sequencing, or targeted next-generation sequencing on tissue biopsies from tumors harboring activating FGFR2 alterations progressing pan-FGFR–selective inhibitors, collected in prospective UNLOCK program. FGFR2::BICC1 Ba/F3 and patient-derived xenograft models were used for functional studies. Results: Thirty-six included. In cholangiocarcinoma, at both reversible (e.g., pemigatinib erdafitinib) irreversible inhibitor futibatinib, polyclonal kinase domain mutations frequent (14/27 patients). Tumors other than cholangiocarcinoma shared same mutated residues, but polyclonality was rare (1/9 At 14 residues mutated—after only molecular brake N550 gatekeeper V565. Off-target PI3K/mTOR MAPK pathways found 11 patients, often together on-target mutations. progression a first inhibitor, 12 received futibatinib lirafugratinib (irreversible inhibitors), variable depending previous mechanisms. Two TSC1 PIK3CA benefited everolimus. cell viability assays pharmacologic studies xenografts, retained better activity against mutations, active recalcitrant V565L/F/Y. Conclusions: malignancies are characterized by high intra- interpatient heterogeneity, particularly cholangiocarcinoma. Resistance can be overcome sequential, molecularly oriented treatment strategies across tumors.

Language: Английский

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Discovery of STX-721, a Covalent, Potent, and Highly Mutant-Selective EGFR/HER2 Exon20 Insertion Inhibitor for the Treatment of Non-Small Cell Lung Cancer

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

After L858R and ex19del epidermal growth factor receptor (EGFR) mutations, ex20ins mutations are the third most common class of driver-mutations in non-small cell lung cancer (NSCLC). Unfortunately, first-, second-, third-generation EGFR tyrosine kinase inhibitors (TKIs) generally ineffective for patients due to insufficient mutant activity selectivity over wild-type EGFR, leading dose-limiting toxicities. While significant advances recent years have been made toward identifying potent inhibitors, vs remains a challenge. STX-721 (53) is potent, irreversible inhibitor majority EGFR/HER2 mutants demonstrates excellent both vitro vivo. currently phase 1/2 clinical trials ex20ins-driven NSCLC.

Language: Английский

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Discovery of Pyrrolopyrazine Carboxamide Derivatives as Potent and Selective FGFR2/3 Inhibitors that Overcome Mutant Resistance

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 68(3), P. 3886 - 3899

Published: Jan. 31, 2025

Fibroblast growth factor receptors (FGFRs) are established oncogenic drivers in various solid tumors. However, the approved FGFR inhibitors face challenges with acquired resistance and dose-limiting adverse effects associated FGFR1/4 inhibition, limiting therapeutic efficacy. Herein, we systematically explored linker electrophile moieties based on pyrrolopyrazine carboxamide core identified aniline α-fluoroacrylamide as an effective covalent warhead. Compound 10 potently inhibited FGFR2 FGFR3, even context of common inhibitor-resistance mutations, including gatekeeper, molecular brake, activation loop regions. spared other kinases without causing diarrhea serum phosphate elevation vivo. Oral administration compound induced tumor stasis or regression SNU-16 gastric cancer model favorable pharmacokinetics robust pharmacodynamic suppression.

Language: Английский

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The future of pharmaceuticals: Artificial intelligence in drug discovery and development

Journal of Pharmaceutical Analysis, Journal Year: 2025, Volume and Issue: unknown, P. 101248 - 101248

Published: Feb. 1, 2025

Language: Английский

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Alchemical Transformations and Beyond: Recent Advances and Real-World Applications of Free Energy Calculations in Drug Discovery

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: 64(19), P. 7214 - 7237

Published: Oct. 3, 2024

Computational methods constitute efficient strategies for screening and optimizing potential drug molecules. A critical factor in this process is the binding affinity between candidate molecules targets, quantified as free energy. Among various estimation methods, alchemical transformation stand out their theoretical rigor. Despite challenges force field accuracy sampling efficiency, advancements algorithms, software, hardware have increased application of energy perturbation (FEP) calculations pharmaceutical industry. Here, we review practical applications FEP discovery projects since 2018, covering both ligand-centric residue-centric transformations. We show that relative steadily achieved chemical real-world applications. In addition, discuss alternative physics-based simulation incorporation deep learning into calculations.

Language: Английский

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Clinical Developments and Challenges in Treating FGFR2-Driven Gastric Cancer

Biomedicines, Journal Year: 2024, Volume and Issue: 12(5), P. 1117 - 1117

Published: May 17, 2024

Recent advances in the treatment of gastric cancer (GC) with chemotherapy, immunotherapy, anti-angiogenic therapy and targeted therapies have yielded some improvement survival outcomes; however, metastatic GC remains a lethal malignancy amongst leading causes cancer-related mortality worldwide. Importantly, ongoing molecular characterisation GCs continues to uncover potentially actionable targets. Among these, aberrant FGFR2-driven signalling, predominantly arising from FGFR2 amplification, occurs approximately 3–11% GCs. However, whilst several inhibitors FGFR been clinically tested to-date, there are currently no approved FGFR-directed for GC. In this review, we summarise significance as an therapeutic target GC, examine recent pre-clinical clinical data supporting use small-molecule inhibitors, antibody-based therapies, well novel approaches such proteolysis-targeting chimeras (PROTACs) targeting these tumours, discuss challenges opportunities associated their development.

Language: Английский

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Discovery of BW710 as a Potent, Selective and Orally Bioavailable Fibroblast Growth Factor Receptor 2 (FGFR2) Inhibitor

European Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: 287, P. 117339 - 117339

Published: Feb. 1, 2025

Language: Английский

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De novo in silico screening of natural products for antidiabetic drug discovery: ADMET profiling, molecular docking, and molecular dynamics simulations

In Silico Pharmacology, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 17, 2025

Language: Английский

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Distinct allosteric networks in CDK4 and CDK6 in the cell cycle and in drug resistance

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

Abstract Cyclin-dependent kinases 4 and 6 (CDK4 CDK6) are key regulators of the G1-S phase transition in cell cycle. In cancer cells, CDK6 overexpression often outcompetes CDK4 driving cycle progression, contributing to resistance against CDK4/6 inhibitors (CDK4/6i). This suggests distinct functional conformational differences between these two kinases, despite their striking structural sequence similarities. Understanding mechanisms that differentiate is crucial, as CDK4/6i—frequently linked overexpression—remains a significant therapeutic challenge. Notably, upregulated CDK4/6i-resistant cancers rapidly proliferating hematopoietic stem underscoring its unique regulatory roles. We hypothesize dynamics explain phosphorylation retinoblastoma protein, Rb, inhibitor efficacy, control. leads us question how dissimilar encode actions . To elucidate differential activities, molecular mechanisms, binding, we combine biochemical assays (MD) simulations. discover have allosteric networks connecting β3-αC loop G-loop. exhibits stronger coupling shorter path lengths regions, resulting higher kinase activity upon cyclin binding impacting specificity. also an unrecognized role unstructured C-terminus, which allosterically connects stabilizes R-spine, facilitating slightly activity. Our findings bridge gap similarity divergence CDK6, advancing understanding regulation biology. Graphical abstract

Language: Английский

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