Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5489 - 5489

Published: May 17, 2024

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies peptides, along innovative approaches use of degraders protein interaction inhibitors, which recently demonstrated clinical progress potential in overcoming resistance. Nevertheless, kinase-targeted encounter significant hurdles, including drug resistance, greatly impacts benefits patients, well concerning toxicity when combined immunotherapy, restricts full utilization current treatment modalities. Despite these challenges, development remains highly promising. The extensively studied tyrosine family has 70% its stages development, while 30% inadequately explored. Computational technologies play a vital role accelerating novel repurposing existing drugs. Recent FDA-approved SMKIs underscore importance blood-brain barrier permeability long-term patient benefits. This review provides comprehensive summary recent based mechanisms action targets. We summarize latest developments new explore emerging inhibition from perspective. Lastly, we outline obstacles future prospects inhibition.

Language: Английский

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First-In-Human Phase I Study of Tinengotinib (TT-00420), a Multiple Kinase Inhibitor, as a Single Agent in Patients With Advanced Solid Tumors

The Oncologist, Journal Year: 2024, Volume and Issue: 29(4), P. e514 - e525

Published: Jan. 31, 2024

Abstract Purpose This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial receptors, Aurora A/B, in patients with advanced solid tumors. Patients Methods received orally daily 28-day cycles. Dose escalation was guided by Bayesian modeling using overdose control. The primary objective to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), recommended for expansion (DRDE). Secondary objectives included pharmacokinetics efficacy. Results Forty-eight were enrolled (dose escalation, n = 40; expansion, 8). MTD not reached; DRDE 12 mg daily. DLTs palmar-plantar erythrodysesthesia syndrome (8 mg, 1) hypertension (15 2). most common treatment-related adverse event (50.0%). In 43 response-evaluable patients, 13 (30.2%) achieved partial response (PR; 7) or stable disease (SD) ≥ 24 weeks (n 6), including 4/11 (36.4%) FGFR2 mutations/fusions cholangiocarcinoma (PR 3; SD 1), 3/3 (100.0%) hormone receptor (HR)-positive/HER2-negative breast cancer 2; 2/5 (40.0%) triple-negative (TNBC; PR 1; 1/1 castrate-resistant prostate (CRPC; PR). Four (33.3%; HR-positive/HER2-negative cancer, TNBC, cholangiocarcinoma) treated at had PRs. Tinengotinib’s half-life 28-34 hours. Conclusions Tinengotinib well favorable pharmacokinetic characteristics. Preliminary findings indicated potential clinical benefit FGFR inhibitor-refractory cholangiocarcinoma, HER2-negative (including TNBC), CRPC. Continued evaluation is warranted II trials.

Language: Английский

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A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma

Annals of Oncology, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 1, 2024

Language: Английский

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Therapies targeting triple-negative breast cancer: a perspective on anti-FGFR

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: March 11, 2025

Triple-negative breast cancer (TNBC) is one of the subtypes with worst prognosis due to tumour heterogeneity and lack appropriate treatment. This condition a consequence distinctive microenvironment (TME). The TME associated factors such as promotion proliferation, angiogenesis, inhibition apoptosis, suppression immune system drug resistance. Therefore, remodelling critical for treatment TNBC. A key role in formation played by fibroblast growth factor/fibroblast factor receptor(FGF/FGFR) signalling pathway. Thus, FGFRs may be potential target treating Over-activated promote growth, migration resistance TNBC influencing onset events, angiogenesis rejection. thorough comprehension FGF/FGFR pathway’s mechanism action development could offer valuable insights discovering new therapeutic strategies targets. Inhibiting axis potentially hinder its disrupting crucial biological processes TME, evasion. review evaluates inhibiting strategy It explores prospects developing related approaches. study research application aim provide guidance further facilitate innovative approaches targeting

Language: Английский

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Safety and Activity of Fibroblast Growth Factor Receptor Inhibitors in Advanced Malignancies: A Pooled Analysis of Early-Phase Clinical Trials

JCO Precision Oncology, Journal Year: 2025, Volume and Issue: 9

Published: April 1, 2025

PURPOSE Aberrant signaling through the fibroblast growth factor receptor ( FGFR ) due to activating somatic alterations has been associated with multiple malignancies. inhibitors (FGFRi) distinct profiles recently entered standard of care. This work summarizes experience a dedicated clinical trial unit FGFRi developed in last decade within context trials. METHODS Demographic and data were collected for patients enrolled FGFR-targeting phase I II trials conducted at Sarah Cannon Research Institute, United Kingdom between January 2012 August 2023. RESULTS Fifty-four across seven identified: 50% male; median age 55 years. An alteration was present 81% cases; rearrangements, amplifications, mutations 59%, 43%, 9.1% cases, respectively, coexisting 27%. The most frequent primary tumors cholangiocarcinomas (31%), urothelial (15%), colorectal (15%); 85% FGFRi-naïve. common adverse events (AEs) hyperphosphatemia (42%), dry mouth (35%), fatigue (24%), mucositis nail changes (22%), palmar-plantar erythrodysesthesia (20%), significant differences pan-FGFRi FGFR-2i. rate G3 AEs 22%; no G4-5 observed. time on treatment 3.5 months (0.2-72.8). Higher disease control observed presence any alteration, compared all-comers (odds ratio [OR], 7; P = .0226). objective response 38%, 25%, 25% gene amplification, mutations, respectively. duration 2.3 (1.6-7.7). After follow-up 20 (95% CI, 12.9 71.8), progression-free survival (mPFS) 3.2 1.9 4.6) overall 13 6.4 19.6). PFS significantly different by response, status, tumor type. Patients who experienced G2-3 AE more likely achieve (OR, 5.24; .0256). CONCLUSION are effective strategies advanced solid harboring alterations, manageable toxicities patients.

Language: Английский

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Chemical reprogramming of liver cancer cells through targeting Aurora kinases

Science China Life Sciences, Journal Year: 2025, Volume and Issue: unknown

Published: April 24, 2025

Language: Английский

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Evolving Paradigms in the Systemic Treatment of Advanced Gallbladder Cancer: Updates in Year 2022

Cancers, Journal Year: 2022, Volume and Issue: 14(5), P. 1249 - 1249

Published: Feb. 28, 2022

Gallbladder cancer (GBC) is a biological, anatomical, and clinically distinct subset of biliary tract cancers (BTC), which also include extra- intra-hepatic cholangiocarcinoma. The advent next-generation sequencing (NGS) clearly shows that GBC genetically different from Although relatively rare cancer, it highly aggressive carries grave prognosis. To date, complete surgical resection remains the only path for cure but limited to patients with early-stage disease. majority are diagnosed at an advanced, inoperable stage when systemic treatment administered as attempt enable surgery or palliation. Gemcitabine platinum-based chemotherapies have been main modality unresectable, locally metastatic gallbladder cancer. However, over past decade, paradigm has evolved. These introduction newer chemotherapeutic strategies after progression on frontline chemotherapy, incorporation targeted therapeutics towards driver mutations genes including HER2, FGFR, BRAF, well approaches unleash host anti-tumor immunity using immune checkpoint inhibitors. Notably, due rarity BTC in general, most clinical trials included both cholangiocarcinomas. Here, we provide review pathogenesis GBC, current options focusing specifically tailored its genetic mutations, emerging based promising recent studies.

Language: Английский

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Tinengotinib (TT-00420), a Novel Spectrum-Selective Small-Molecule Kinase Inhibitor, Is Highly Active Against Triple-Negative Breast Cancer

Molecular Cancer Therapeutics, Journal Year: 2022, Volume and Issue: 22(2), P. 205 - 214

Published: Oct. 12, 2022

Triple-negative breast cancer (TNBC) is a highly heterogeneous lacking actionable targets. Using phenotypic screen of TNBC cells, we discovered novel multiple kinase inhibitor tinengotinib (TT-00420) that strongly inhibited Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R in biochemical assays. Exposure to specifically proliferation across all subtypes vitro vivo, while leaving luminal cells intact. Incubation HCC1806 with led dose-dependent downregulation genes essential for cell growth proliferation. Studies revealed the potential mechanism action involved, predominantly, inhibition A or B activity, other pathways contributed suppression potency activity. In treatment lines vivo administration syngeneic model resulted up-regulation CXCL10 11 diminished tumor-associated macrophage (TAM) infiltration. Tinengotinib represents combinatorial inhibitory treat TNBC. The phase I trial was completed (ClinicalTrials.gov identifier: NCT03654547).

Language: Английский

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Harnessing unprotected deactivated amines and arylglyoxals in the Ugi reaction for the synthesis of fused complex nitrogen heterocycles

Beilstein Journal of Organic Chemistry, Journal Year: 2024, Volume and Issue: 20, P. 1758 - 1766

Published: July 25, 2024

Piperazines and diazepines are examples of nitrogen heterocycles present in many marketed drugs highlighting their importance the discovery novel bioactive compounds. However, synthesis often faces challenges, including complex functionalization lengthy reaction sequences. Multicomponent reactions, notably Ugi reaction, have emerged as powerful tools to address these hurdles. Here, we demonstrated possibility using combination arylglyoxals carboxylic acids tethered nonprotected deactivated amines a strategy for fused heterocycles. The limited nucleophilic character amino group anthranilic acid, indole-2-carboxylic pyrrole-2-carboxylic acid or N -phenylglycine has allowed use compounds without triggering competitive reactions. additional functional resulting adduct can be leveraged different post-condensation strategies easily generate multiple benzodiazepinone piperazinone cores.

Language: Английский

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Fibroblast growth factor therapies in biliary tract cancers: current and future state

Expert Opinion on Investigational Drugs, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 11

Published: Dec. 4, 2024

Introduction Cholangiocarcinoma is the rare and aggressive tumor with poor prognosis limited therapeutic options. Recently, there have been promising developments in molecular targeted therapies for patients following progression of first-line chemotherapy immunotherapy combinations. Dysregulation fibroblast Growth Factor Receptor (FGFR) signaling significantly associated tumorigenesis intrahepatic cholangiocarcinoma has identified as a targetable alteration. This was possible through discovery crucial insights into biochemical mechanisms pathophysiology FGFR pathway.

Language: Английский

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