These efforts underscore the importance of integrating scaffolds from promising candidate and clinically approved drugs to advance next-generation kinase inhibitors targeting breast cancer subtypes, thereby overcoming challenges and improving structural optimization outcomes.
Abstract
Breast cancer remains a leading cause of morbidity and mortality among women worldwide, necessitating innovative therapeutic strategies to overcome drug resistance and tumor heterogeneity. Breast cancer is a heterogeneous disease in which dysregulated tyrosine kinase signaling drives proliferation, survival, metastasis, and resistance. Tyrosine kinase inhibitors (TKIs) are pivotal targeted agents in breast cancer therapy, owing to their ability to modulate critical signaling pathways implicated in cancer progression. This review summarizes medicinal-chemistry strategies for designing small-molecule TKIs, integrating binding-mode classifications with scaffold selection and structure-guided optimization. Representative advances include HER2-selective, dual-RTK approaches such as EGFR/VEGFR-2 and EGFR/HER2 designs that enhance activity and overcome resistance. Emerging strategies, such as lapatinib-based PROTACs, demonstrate effective EGFR/HER2 degradation and strong antiproliferative activity in HER2-driven models, and have expanded beyond the HER family to include targets such as c-MET, FGFR, BTK, FAK, SRC, and JAK, highlighting their potential against the aggressive triple-negative breast cancer subtype. Studies featuring reversible and irreversible inhibitors, multi-targeted ligands, and covalent kinase inhibitors targeting BC are presented. These efforts underscore the importance of integrating scaffolds from promising candidate and clinically approved drugs to advance next-generation kinase inhibitors targeting breast cancer subtypes, thereby overcoming challenges and improving structural optimization outcomes.
Cancer remains one of the leading causes of mortality worldwide, with
conventional therapies often limited by systemic toxicity, therapeutic resistance, and tumor heterogeneity.
Multi-target drug discovery has emerged as a contemporary strategy to overcome
these challenges, particularly through multi-kinase inhibitors and bispecific antibodies that simultaneously
modulate multiple oncogenic pathways.
This review integrates evidence from preclinical investigations, pivotal clinical trials,
regulatory approvals, and key patent literature underpinning the development of multi-target
anticancer agents. Representative multi-kinase inhibitors-including sorafenib, sunitinib, lenvatinib,
cabozantinib, and regorafenib-are critically analyzed with respect to their molecular
targets, therapeutic advantages, clinical performance, and associated intellectual property. Patented
innovations covering kinase inhibition platforms, antibody engineering, and biomarkerbased
cancer detection are also discussed.
MKIs act by concurrently inhibiting multiple signaling kinases, such as vascular
endothelial growth factor receptors, platelet-derived growth factor receptors, fibroblast
growth factor receptors, mesenchymal-epithelial transition factor, rearranged during
transfection, and rapidly accelerated fibrosarcoma, thereby suppressing angiogenesis,
limiting compensatory signaling, and addressing tumor heterogeneity. Clinical trials
demonstrate significant survival benefits in hepatocellular carcinoma, renal cell carcinoma,
and thyroid cancer. Parallel advances in patented bispecific antibodies and epigenetic
diagnostic technologies further expand the therapeutic and diagnostic landscape.
Multi-targeting strategies delay resistance, reshape the tumor microenvironment,
and improve outcomes, particularly when combined with immunotherapies or chemotherapies.
However, challenges persist, including off-target toxicity, pharmacokinetic variability, high
development costs, and limited accessibility. Patent trends reveal a growing emphasis
on biomarker-guided patient selection, novel antibody formats, and rational combination
therapies.
MKIs and bispecific antibodies represent transformative modalities in modern oncology,
supported by robust clinical evidence and extensive patent activity.
Thirumalaikumaran Rathinam, S. Reddy, Yella Sirisha et al.· Recent Patents on Anti-Cance...· 0 citations
ABSTRACT
Breast cancer remains the most common cancer among women worldwide, characterized by significant molecular heterogeneity. Advances in targeted therapy and immunotherapy have transformed treatment approaches, offering promising new options for patients. Targeted therapies are designed to inhibit the key pathways that drive tumor growth and survival. The cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphatidylinositol-3 kinase (PI3K) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and other treatments have significantly advanced treatment, delaying progression and extending survival for some subtypes of breast cancer. Nevertheless, targeted therapeutic agents have not yet demonstrated significant clinical efficacy in the treatment of triple-negative breast cancer (TNBC). Meanwhile, immunotherapy has emerged as a complementary approach. Immune checkpoint inhibitors (ICIs) have demonstrated notable efficacy in subsets of TNBC and are under exploration in other breast cancer subtypes, including hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2-) and HER2-positive disease. Furthermore, innovative strategies such as anticancer vaccines and adoptive T-cell therapy offer potential for prolonged immune engagement and tumor eradication. This review provides an overview of current progress in targeted therapies and immunotherapy for breast cancer, highlighting their mechanisms, clinical utility, and challenges. By integrating knowledge from recent advancements, this review seeks to guide future research and clinical practice toward improved and personalized care for breast cancer patients.
Song Wu, Pangzhou Chen, Wen Zhou et al.· Chinese Medical Journal· 0 citations
This work systematically reviews pan-cancer HER2-related oncogenic mechanisms and the full spectrum of targeted regimens offering mechanistic and clinical references for precision therapy and new drug research of HER2-positive solid tumors.
Congyu Wang· Theoretical and Natural Scie...· 0 citations
Acquired resistance to third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) presents a formidable challenge in the treatment of non-small cell lung cancer (NSCLC). Despite the remarkable efficacy of these agents, resistance inevitably develops, typically within approximately 10 months of treatment initiation. This review elucidates the multifaceted mechanisms driving this resistance, broadly categorized into on-target EGFR-dependent alterations and off-target EGFR-independent bypass pathway activations. On-target mechanisms include the emergence of tertiary EGFR mutations, most notably C797S, which disrupts TKI binding. Off-target mechanisms encompass the activation of alternative signaling pathways such as MET and HER2/HER3 amplification, as well as histological transformations and complex changes within the tumor microenvironment. Furthermore, recent discoveries highlight the role of epigenetic dysregulation and metabolic reprogramming in fostering resistance. To counter this pervasive adaptability, advanced diagnostic methodologies, including liquid biopsy and high-resolution omics technologies, are crucial for real-time molecular profiling. The field is actively exploring emerging combination therapeutic strategies to circumvent these diverse resistance pathways, aiming to prolong clinical benefits and improve patient outcomes. The persistent emergence of resistance underscores that current targeted therapies, while revolutionary, are primarily disease-modifying rather than curative, necessitating continuous innovation to overcome the inherent biological challenge of tumor adaptability and heterogeneity.
Gu-Ha A-Lai, Lian Li, G. Ma et al.· Frontiers in Cell and Develo...· 0 citations
This review examines the clinical development of palbociclib, ribociclib, and abemaciclib across both early-stage and metastatic settings, revealing clinically meaningful differences in efficacy that challenge the notion of a uniform class effect.
Breast cancer continues to be one of the top causes of cancer death globally, with triple‐negative breast cancer (TNBC) being the most aggressive variety as it has a much poorer prognosis, strong propensity for metastases, and fewer effective targeted therapies available. The increased expression of the epidermal growth factor receptor (EGFR) is essential for cancer cell growth, survival, migration, and drug resistance making EGFR a good target for therapy. However, the effectiveness of EGFR inhibitors has been limited because of heterogeneity of tumors, low occurrence of activating EGFR mutations, and activity of compensatory pathways. This mini‐review aims to summarize new findings on the design of small molecules that inhibit EGFR including pyrimidine‐5‐carbonitrile, thiazolyl‐pyrazolines, quinoxaline, quinazoline–sulfonamide hybrids, xanthine–chalcone conjugates, aminoquinolines, and pyridazine analogues. Their pharmacological properties, interactions with EGFR in silico and important structural characteristics responsible for their therapeutic action will also be discussed. Possible approaches for overcoming acquired resistance, including covalent and allosteric inhibitors, dual‐acting compounds, and combination therapies will be presented here.
