Future medicinal chemistry最新文献_第2页

Rational drug design for Alzheimer's disease: from approved therapies to next-generation clinical candidates and AI-guided innovation. 阿尔茨海默病的合理药物设计：从批准的疗法到下一代临床候选药物和人工智能引导的创新。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-09-01 Epub Date: 2026-08-10 DOI: 10.1080/17568919.2026.2714022

Sana Saffour, Turgut Seckin Gul, Halise Inci Gul

{"title":"Rational drug design for Alzheimer's disease: from approved therapies to next-generation clinical candidates and AI-guided innovation.","authors":"Sana Saffour, Turgut Seckin Gul, Halise Inci Gul","doi":"10.1080/17568919.2026.2714022","DOIUrl":"10.1080/17568919.2026.2714022","url":null,"abstract":"Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by multifactorial pathology, including amyloid-β (Aβ) aggregation, tau hyperphosphorylation, oxidative stress, neuroinflammation, and synaptic dysfunction. Despite extensive research, currently approved treatment provides only symptomatic relief, while recently approved disease-modifying monoclonal antibodies have shown limited benefits. Ongoing clinical investigations have shifted toward multi-target directed ligands (MTDLs), RNA-based therapies, immunotherapies, and vaccines. Some approved drugs that have established safety profiles are being repurposed to address the disease's neuropsychiatric symptoms or modulate AD pathological changes. Integrating diverse pharmacophores, such as curcumin, resveratrol, chromone, and indole, within a single skeleton is anticipated to exert multi-modal modifying properties. In parallel, optimization of ADME properties, particularly blood-brain barrier (BBB) permeation and efflux modulation, remains a major obstacle in AD drug design. The incorporation of artificial intelligence (AI) and machine learning (ML) is expected to enhance the prediction of pharmacokinetic, pharmacodynamic, and toxicity parameters.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2425-2443"},"PeriodicalIF":3.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

VEGFR-2 as a druggable target: recent advances (2025) in the development of five-membered heterocyclic anticancer agents. VEGFR-2作为可药物靶点：五元杂环抗癌药物的最新进展（2025）

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-09-01 DOI: 10.1080/17568919.2026.2726194

Mohamed M Khalifa, Ibtehal Nasser Salman, Reyadh Jassem

{"title":"VEGFR-2 as a druggable target: recent advances (2025) in the development of five-membered heterocyclic anticancer agents.","authors":"Mohamed M Khalifa, Ibtehal Nasser Salman, Reyadh Jassem","doi":"10.1080/17568919.2026.2726194","DOIUrl":"https://doi.org/10.1080/17568919.2026.2726194","url":null,"abstract":"The global burden of cancer continues to escalate, with angiogenesis representing a critical driver of tumor progression and metastasis. Vascular endothelial growth factor receptor-2 (VEGFR-2) stands as the principal mediator of angiogenic signaling, making it an established and compelling therapeutic target. Despite the clinical success of first-generation inhibitors, their long-term efficacy remains limited by off-target toxicities, suboptimal pharmacokinetic profiles, and the inevitable emergence of drug resistance through multiple adaptive mechanisms. These limitations underscore an urgent need for next-generation inhibitors engineered with enhanced selectivity, improved safety margins, and the capacity to circumvent resistance pathways. This comprehensive review systematically examines recent advances in the rational design, synthesis, and biological evaluation of five-membered heterocyclic scaffolds, thiadiazol, oxazole, thiazole, and pyrrole, as well as pyrazole and imidazole-based inhibitors as novel VEGFR-2 inhibitors. Each section analyzes the molecular hybridization strategies employed to integrate essential pharmacophoric features, including heteroaromatic hinge-binding motifs, hydrogen bond donor-acceptor systems for DFG motif engagement, and terminal hydrophobic groups for allosteric pocket occupancy. Detailed structure-activity relationship discussions elucidate how substituent variations influence potency, selectivity, and physicochemical properties.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1-20"},"PeriodicalIF":3.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Latest developments in small molecule inhibitors of cysteine protease B as antileishmanial drugs. 半胱氨酸蛋白酶B小分子抑制剂抗利什曼病的最新进展。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-09-01 Epub Date: 2026-08-07 DOI: 10.1080/17568919.2026.2714018

Karla Joane da Silva Menezes, Sonaly Lima Albino, João Vitor Vieira da Silva, Éric de Oliveira Rios, Rafaella Alves da Silva Barbosa, Juan D Rodríguez-Macías, Edgar Alexander Marquez Brazon, Fátima Nogueira, Sofia Cortes, Ricardo Olimpio de Moura, Igor José Dos Santos Nascimento

{"title":"Latest developments in small molecule inhibitors of cysteine protease B as antileishmanial drugs.","authors":"Karla Joane da Silva Menezes, Sonaly Lima Albino, João Vitor Vieira da Silva, Éric de Oliveira Rios, Rafaella Alves da Silva Barbosa, Juan D Rodríguez-Macías, Edgar Alexander Marquez Brazon, Fátima Nogueira, Sofia Cortes, Ricardo Olimpio de Moura, Igor José Dos Santos Nascimento","doi":"10.1080/17568919.2026.2714018","DOIUrl":"10.1080/17568919.2026.2714018","url":null,"abstract":"Leishmaniasis is a neglected tropical disease, transmitted by the bite of infected female sandflies and affecting the poor population. Current pharmacotherapy has remained largely unchanged for decades, and there are parasitic strains resistant to these conventional treatments. Thus, there is an urgent need to identify molecular targets to guide the rational design of new drugs. Thus, cysteine protease B (CPB) emerges as a promising target due to its roles in pathogenesis, virulence, and in modulating the host immune response. Given this potential, this review presents recent advances in CPB inhibitors, examining scaffolds, their structure-activity relationships (SARs), and the structural elements that confer selectivity for the parasitic target. Aziridine analogs and dipeptidyl nitriles stand out, and the SAR studies presented here indicate that structural modifications in the P1, P2, and P3 binding subsites influence compound affinity, thereby optimizing molecular fit in the enzyme. The stereochemical configuration (S,S) of the inhibitors is also essential for potency. Regarding selectivity, the Tyr210 residue is present in CPB but not in human cathepsin L. Taken together, these structural and mechanistic findings offer new perspectives for advancing medicinal chemistry targeting CPB, in the development of safer, more selective, and more effective antileishmanial agents.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2389-2402"},"PeriodicalIF":3.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148684016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chalcone-indole hybrid scaffolds as promising anticancer drug candidates: a mini-review. 查尔酮-吲哚杂化支架作为有前途的抗癌候选药物：综述。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-09-01 Epub Date: 2026-08-20 DOI: 10.1080/17568919.2026.2714032

Yafei Zhuang, Yanjing Cheng, Danchen Zhao, Jun Yu, Lianlian Chen

{"title":"Chalcone-indole hybrid scaffolds as promising anticancer drug candidates: a mini-review.","authors":"Yafei Zhuang, Yanjing Cheng, Danchen Zhao, Jun Yu, Lianlian Chen","doi":"10.1080/17568919.2026.2714032","DOIUrl":"10.1080/17568919.2026.2714032","url":null,"abstract":"Cancer treatment is hampered by severe systemic side effects, poor tumor selectivity, and multidrug resistance (MDR). Molecular hybridization integrates chalcone and indole, two privileged antitumor pharmacophores, into one scaffold to generate chalcone-indole hybrids that synergistically enhance antitumor potency, improve tumor targeting, and reverse MDR. This mini-review analyzes literature from 2020 to 2026 on chalcone-indole anticancer hybrids. Based on structural modification patterns, the reported hybrids are categorized into four subgroups: simple substituted, α/β-position modified, N-1 fatty acid-substituted, and multi-pharmacophore fused hybrids. For each category, we summarize structure-activity relationships (SARs), antiproliferative activity, selective toxicity, molecular mechanisms, and in vivo xenograft performance. Most lead compounds exert tumor-suppressive effects via tubulin polymerization inhibition, G2/M cell cycle arrest, ROS overaccumulation, and mitochondrial-dependent apoptosis. Representative hybrids 10a, 12a, 21a, and 25a exhibit remarkable efficacy against drug-resistant colorectal, lung, and breast tumors with favorable in vivo safety. We highlight the application potential of different subtypes for specific malignancies, including α/β-modified analogues for resistant colorectal cancer, N-1 fatty acid-platinum conjugates for platinum-resistant lung cancer, NLRP3 inhibitor 7a for oral cancer, and multi-pharmacophore fused derivatives for broad-spectrum activity. Current bottlenecks limiting clinical transformation are discussed. This review provides structural design rules for developing novel chalcone-indole targeted anticancer agents.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2463-2476"},"PeriodicalIF":3.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Design, synthesis and dual anticancer and antibacterial evaluation of novel 1,3,4-oxadiazole-2-thiol derivatives targeting EGFR and DNA Gyrase B: integrated docking, DFT and ADMET studies. 靶向EGFR和DNA Gyrase B的新型1,3,4-恶二唑-2-硫醇衍生物的设计、合成及其抗癌和抗菌双重评价：集成对接、DFT和ADMET研究。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-09-01 Epub Date: 2026-08-06 DOI: 10.1080/17568919.2026.2714027

Ila M Ram, Jay B Maheta, Darshna K Lakhnotra, Nargis H Shaikh, Prince A Dave, Parth Thakor, Shivani Lakhani, Anjali B Thakkar, Yogesh O Bhola

{"title":"Design, synthesis and dual anticancer and antibacterial evaluation of novel 1,3,4-oxadiazole-2-thiol derivatives targeting EGFR and DNA Gyrase B: integrated docking, DFT and ADMET studies.","authors":"Ila M Ram, Jay B Maheta, Darshna K Lakhnotra, Nargis H Shaikh, Prince A Dave, Parth Thakor, Shivani Lakhani, Anjali B Thakkar, Yogesh O Bhola","doi":"10.1080/17568919.2026.2714027","DOIUrl":"10.1080/17568919.2026.2714027","url":null,"abstract":"Novel 1,3,4-oxadiazole-2-thiol derivatives (8a-j) were synthesized via multistep reactions and characterized using IR, 1H NMR, and 13C NMR spectroscopy. The compounds were evaluated for dual anticancer and antibacterial activities through computational and experimental approaches. Molecular docking against EGFR (1M17) and DNA gyrase B (2XCT) revealed compound 8h as the most potent EGFR inhibitor (-7.528 kcal/mol), surpassing methotrexate (-7.448 kcal/mol), while compound 8c demonstrated superior DNA gyrase B binding (-7.263 kcal/mol), exceeding ciprofloxacin (-6.11 kcal/mol) by 19%. In vitro cytotoxicity against A549 human lung carcinoma cells identified compound 8c as the most active anticancer agent (IC50 = 14.59 ± 0.19 µg/mL), comparable to methotrexate (IC50 = 11.82 ± 1.22 µg/mL). Antibacterial screening against S. aureus, E. coli, and K. pneumoniae revealed compound 8d as the most effective broad-spectrum agent (MIC = 25 µg/mL across all strains), demonstrating 2-fold superior activity against S. aureus versus ciprofloxacin. Comprehensive DFT calculations on compound 8c elucidated frontier orbital energies (HOMO-LUMO gap: 4.7528 eV), global reactivity descriptors, optimized geometry, Mulliken charge distribution, and topological properties (MEP, RDG, ELF, LOL). ADMET profiling revealed favorable drug-likeness with 0-1 Lipinski violations, optimal lipophilicity (cLogP: 2.7-3.97), and good predicted oral absorption (57-64%). These findings establish 1,3,4-oxadiazole-2-thiol derivatives as promising dual-action therapeutic scaffolds.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2319-2335"},"PeriodicalIF":3.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Beyond the ATP-binding pocket: emerging strategies in kinase targeting from allosteric inhibition to targeted protein degradation. 超越atp结合口袋：从变构抑制到靶向蛋白降解的激酶靶向新策略。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-09-01 Epub Date: 2026-08-13 DOI: 10.1080/17568919.2026.2718758

Mei Zhou, Linshan Li, Xiaojuan Tang, Yazhu Zhao, Wei Zhang

{"title":"Beyond the ATP-binding pocket: emerging strategies in kinase targeting from allosteric inhibition to targeted protein degradation.","authors":"Mei Zhou, Linshan Li, Xiaojuan Tang, Yazhu Zhao, Wei Zhang","doi":"10.1080/17568919.2026.2718758","DOIUrl":"10.1080/17568919.2026.2718758","url":null,"abstract":"Protein kinases are central regulators of cellular signaling and remain a major target class in precision medicine. While ATP-competitive inhibitors-including conformation-selective and covalent agents-have delivered substantial clinical benefit, durable responses are frequently limited by the conservation of the ATP pocket and the emergence of resistance mutations (e.g. gatekeeper and solvent-front substitutions), as well as kinase noncatalytic functions that are not addressed by enzymatic inhibition alone. Consequently, kinase drug discovery is expanding beyond orthosteric occupancy toward modalities that reprogram kinase conformations or eliminate the target protein. This Review summarizes the structural and medicinal chemistry principles underlying (i) allosteric inhibition and (ii) proximity-induced degradation, with an emphasis on design logic, structure-activity relationships, and key liabilities in the beyond rule of five space. We further highlight enabling technologies-including structural biology, chemical proteomics, and AI/ML-assisted modeling-that support allosteric site identification, ternary complex engineering, and multi-parameter optimization. Finally, we discuss translational challenges for bifunctional molecules, including permeability, exposure-response relationships, off-target degradation, and safety, and propose practical considerations for developing next-generation selective kinase therapeutics.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"2445-2461"},"PeriodicalIF":3.3,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148759764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Latest developments of spirooxindoles and their derivatives in medicinal chemistry. 螺旋菌吲哚及其衍生物在药物化学中的最新进展。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-08-26 DOI: 10.1080/17568919.2026.2719228

Firoj Hassan, Nadimullah, Sabahat Yasmeen Sheikh, Iqbal Azad, Malik Nasibullah

{"title":"Latest developments of spirooxindoles and their derivatives in medicinal chemistry.","authors":"Firoj Hassan, Nadimullah, Sabahat Yasmeen Sheikh, Iqbal Azad, Malik Nasibullah","doi":"10.1080/17568919.2026.2719228","DOIUrl":"https://doi.org/10.1080/17568919.2026.2719228","url":null,"abstract":"Spirooxindoles represent a pivotal class of heterocyclic compounds known for their diverse and potent biological activities. Naturally occurring spirooxindoles have been isolated from medicinal plants such as Flueggea virosa and Mitragyna speciosa, inspiring extensive research into their synthetic analogs. A variety of synthetic strategies, including multicomponent reactions, cycloaddition processes, and environmentally benign (green chemistry) approaches, have been developed to access structurally diverse spirooxindole derivatives. Recent investigations underscore their broad-spectrum bioactivity, including efficacy against drug-resistant bacterial and fungal pathogens, inhibition of the p53-MDM2 protein-protein interaction, and significant cytotoxicity against various human cancer cell lines. Advances in synthetic methodologies, notably microwave-assisted and catalyst-free protocols, have significantly improved the efficiency, selectivity, and sustainability of spirooxindole synthesis. This study summarizes recent developments in spirooxindole-containing compounds, both naturally isolated and synthetically prepared, reported in the last few years.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1-10"},"PeriodicalIF":3.3,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Synthesis of novel thiazole derivatives linked benzonitrile moiety as potent antimicrobial agents. 新型噻唑类强效抗菌剂的合成。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-08-20 DOI: 10.1080/17568919.2026.2718759

Mariam A Al-Sheikh, Thoraya A Farghaly

{"title":"Synthesis of novel thiazole derivatives linked benzonitrile moiety as potent antimicrobial agents.","authors":"Mariam A Al-Sheikh, Thoraya A Farghaly","doi":"10.1080/17568919.2026.2718759","DOIUrl":"https://doi.org/10.1080/17568919.2026.2718759","url":null,"abstract":"Aim: This study aims to design a new series of thiazoles by combining a thiazole core with a benzonitrile moiety via a suitable linker. Additionally, a hydrazone linker was employed to enhance molecular flexibility and facilitate favorable interactions within the DNA gyrase active site and testing their antimicrobial.Materials and methods: We synthesized a series of thiazole‑linked benzonitrile moiety through the reaction of thiosemicarbazone derivative with α-halocarbonyl reagents in basic refluxing dioxane. The novel derivatives were investigated for their antimicrobial activity.Results and conclusion: All derivatives showed excellent inhibition toward the used bacteria with inhibition zone diameter ranging from 10 to 35 mm. The evaluated thiazole derivatives exhibited superior antibacterial activity compared to antifungal activity, as none demonstrated efficacy against Aspergillus niger. Several derivatives showed antibacterial activity exceeded the reference drugs. Moreover, three derivatives 9, 13e, and 13h showed the same low values of both minimum inhibition concentration and minimum bactericidal concentration with Klebsiella pneumoniae, Staphylococcus aureus and Bacillus subtilis. Moreover, the most active derivative 13e exhibited a notable noncytotoxic effect on WI-38 cells revealing its safety. Finally, we have successfully synthesized nontoxic, antibacterial derivatives. Further research on these derivatives is possible to develop an effective antimicrobial drug.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1-12"},"PeriodicalIF":3.3,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies. 选择性KRAS g12d靶向药物的设计和开发进展与挑战：抑制剂、降解剂和新兴治疗策略。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-08-19 DOI: 10.1080/17568919.2026.2719780

Eunhye Jeon, Jaewon Song, Taebo Sim

{"title":"Progress and challenges in the design and development of selective KRAS G12D-targeted drug discovery: inhibitors, degraders and emerging therapeutic strategies.","authors":"Eunhye Jeon, Jaewon Song, Taebo Sim","doi":"10.1080/17568919.2026.2719780","DOIUrl":"https://doi.org/10.1080/17568919.2026.2719780","url":null,"abstract":"KRAS is one of the most frequently mutated oncogenes in human cancers, with KRAS G12D representing the predominant mutation in pancreatic ductal adenocarcinoma and a major driver of colorectal and lung cancers. Although KRAS was long considered \"undruggable\" due to structural and biochemical constraints, the discovery of the switch-II pocket enabled the development of direct KRAS inhibitors, leading to the clinical success of KRAS G12C-targeted therapies. Building on this breakthrough, advances have been made in KRAS G12D-targeted drug development, including potent non-covalent inhibitors such as MRTX1133, HRS-4642, LY3962673, and INCB161734, as well as RAS(ON) tri-complex inhibitors such as RMC-9805. Pan-RAS and pan-KRAS inhibitors have emerged as a promising strategy to overcome the limitations of mutation-specific KRAS inhibitors, including restricted mutation coverage and acquired resistance. Among the developed pan-RAS inhibitors, RMC-6236 is the most advanced candidate in clinical development. In parallel, targeted protein degradation strategies, particularly PROTAC-based degraders such as ASP3082 and RP03707, have emerged as promising alternatives to overcome resistance and improve therapeutic durability. Combination strategies involving EGFR inhibitors, chemotherapy, and immunotherapy are also expanding clinical potential. This review summarizes recent progress in KRAS G12D-targeted inhibitors and degraders, highlighting current challenges and future opportunities for improving KRAS-directed cancer treatment.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1-16"},"PeriodicalIF":3.3,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chromanone and chromone scaffolds in cancer and metabolic disorders: advances in synthesis, SAR, and developability (2020-2026). 癌症和代谢性疾病中的铬酮和铬酮支架：合成、SAR和可发展性的进展（2020-2026）。

IF 3.3 4区医学

Future medicinal chemistry Pub Date : 2026-08-19 DOI: 10.1080/17568919.2026.2718762

Manisha Nidhar, Muhammad Afzal, Gaurav Gupta, Surya Nath Pandey, Vaishali Goel, Avijit Mazumder, Pavan Goud, Sachin Kumar Singh, Keshav Raj Paudel, Kamal Dua

{"title":"Chromanone and chromone scaffolds in cancer and metabolic disorders: advances in synthesis, SAR, and developability (2020-2026).","authors":"Manisha Nidhar, Muhammad Afzal, Gaurav Gupta, Surya Nath Pandey, Vaishali Goel, Avijit Mazumder, Pavan Goud, Sachin Kumar Singh, Keshav Raj Paudel, Kamal Dua","doi":"10.1080/17568919.2026.2718762","DOIUrl":"https://doi.org/10.1080/17568919.2026.2718762","url":null,"abstract":"Chromanone and chromone are related benzopyran-based scaffolds that offer multiple opportunities for structural modification and medicinal chemistry. This review summarizes studies published from 2020 to 2026 on the synthesis, structure-activity relationships, biological activities, and developability of these compounds in cancer and metabolic disorders. Recent synthetic approaches have enabled the modification of the heterocyclic ring, fused benzene ring, and carbonyl region, as well as the preparation of hybrid, fused, and spiro derivatives of these compounds. In anticancer research, these compounds have demonstrated antiproliferative, pro-apoptotic, cell cycle-modulating, and signaling-related effects. In metabolic disorders, the reported activities of these compounds include the inhibition of carbohydrate-digesting enzymes, improvement of insulin signaling, suppression of hepatic glucose production, and regulation of lipid metabolism. The review also evaluated the strength of the available evidence, noting that many studies remain limited to docking, isolated enzyme assays, or cell-based screening. The available information on physicochemical properties, pharmacokinetics, metabolism, safety, and in vivo efficacy is comparatively limited. Future research should prioritize standardized biological evaluations, robust mechanistic validations, and integrated optimization of potency, selectivity, safety, and pharmacokinetic properties to facilitate the translational development of chromanone- and chromone-based compounds.","PeriodicalId":12475,"journal":{"name":"Future medicinal chemistry","volume":" ","pages":"1-20"},"PeriodicalIF":3.3,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148790670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0