Using generative AI to transform peptide hits into small molecule leads

• Joshua Mills and
• Yu Heng Lau

Beilstein J. Org. Chem. 2026, 22, 672–679, doi:10.3762/bjoc.22.51

• drug targets, serving as rich inspiration for designing small molecule inhibitors which can recapitulate key binding interactions while improving pharmacokinetic properties. With the rapid advancement of artificial intelligence capabilities including powerful generative models, there is significant

• dynamics (MD) and docking (Figure 1). As an illustrative example, Yoshida and co-workers at Shionogi reported the design of small molecule inhibitors of nicotinamide N-methyltransferase [14] and β-herpesvirus proteases [15], starting from cyclic peptide hits obtained by mRNA display with flexible in vitro

Advantages of PROTACs in achieving selective degradation of homologous protein families

• Luxi Yang,
• Xinfei Mao,
• Jingyi Zhang,
• Jing Shu,
• Wenhai Huang,
• Xiaowu Dong,
• Yinqiao Chen and
• Mingfei Wu

Beilstein J. Org. Chem. 2026, 22, 628–661, doi:10.3762/bjoc.22.49

• . Compared with conventional small-molecule inhibitors, PROTACs exhibit notable advantages, particularly in achieving selectivity within highly homologous proteins. The ability to discriminate among members of such families holds broad implications for future disease treatment. In this review, we primarily

• recognized as one of the leading causes of human diseases [3]. Although small-molecule inhibitors [4] remain the most widely used therapeutic agents for the treatment of disorders associated with abnormal protein activity, nearly all disease-relevant scaffolding proteins [5], transcription factors [6], and

• sufficient to trigger rapid ubiquitination [15][16]. Consequently, a PROTAC operates through an event-driven pharmacological paradigm, distinguishing itself from the traditional occupancy-driven model of small-molecule inhibitors [17]. Furthermore, PROTACs function catalytically, requiring only

Towards the targeted protein degradation of CK2: design and synthesis of CAM4066-based PROTACs

• Sophie Day-Riley,
• Sona Krajcovicova,
• Aryaman Raj Sokhal,
• Jan L. Venne,
• Paul Brear,
• Marko Hyvönen,
• Benjamin C. Whitehurst,
• Jason S. Carroll and
• David R. Spring

Beilstein J. Org. Chem. 2026, 22, 611–619, doi:10.3762/bjoc.22.47

• Cambridge Institute, Robinson Way, Cambridge, CB2 0RE, United Kingdom 10.3762/bjoc.22.47 Abstract Human protein kinase CK2 is a constitutively active serine/threonine kinase implicated in numerous cancers. Although ATP-competitive inhibitors such as CX-4945 show therapeutic potential, they are limited by

• . Despite successes with ATP-competitive inhibitors, small-molecule kinase inhibitors can be limited by reversible target engagement, off-target effects, and susceptibility to resistance mechanisms [7]. These challenges have motivated the exploration of alternative therapeutic modalities that move beyond

• . Acknowledgements The authors are grateful to Kristina Kostadinova and Dr Marc de la Roche for the help with the Western Blot analysis, to Dr Eleanor Atkinson and Dr Jessica Iegre for their prior work on CK2 inhibitors, and to Dr Michal Malon for his help with several NMR assignments. We are grateful for the

Design and synthesis of an erdafitinib-based selective FGFR2 degrader

• Yumeng Jin,
• Shidong Wang,
• Sihan Pan,
• Shuqi Huang,
• Weichen Zhou,
• Xiaohao Huang,
• Lei Zheng and
• Lingfeng Chen

Beilstein J. Org. Chem. 2026, 22, 583–591, doi:10.3762/bjoc.22.44

• growth factor receptor 2 (FGFR2) to overcome the issues of drug resistance and adverse reactions associated with traditional inhibitors in the treatment of FGFR2-driven tumors. Erdafitinib was employed as the targeting ligand, and its aliphatic amine site was conjugated with a CRBN E3 ligase ligand to

• cholangiocarcinoma [16][17][18]. Accordingly, research into therapeutics targeting FGFR2 has emerged as a major focus. To treat FGFR2-driven tumors, current research primarily focuses on two distinct classes of inhibitors, namely FGFR pan-inhibitors and FGFR2-selective inhibitors. Among these in Figure 1

• , futibatinib, infigratinib, and erdafitinib, as pan-FGFR inhibitors, exhibit therapeutic efficacy against tumors driven by FGFR2. For advanced cholangiocarcinoma driven by FGFR2, infigratinib and futibatinib are targeted drugs specifically approved for this indication [19]. In contrast, erdafitinib is

Molecular tweezer–peptide conjugates disrupt the protein–protein interaction between survivin and histone H3 essential in mitosis

• Catherine Gsell,
• Philipp Rebmann,
• Karina Opara,
• Christine Beuck,
• Peter Bayer,
• David Bier,
• Ingrid R. Vetter and
• Thomas Schrader

Beilstein J. Org. Chem. 2026, 22, 557–567, doi:10.3762/bjoc.22.41

• and precisely the natural binding site in the wide 14-3-3-cleft [10]. These examples for designed protein–protein interaction (PPI) inhibitors demonstrated that short but highly flexible linkers are imperative to increase selectivity and minimize entropical penalty. The design was strongly supported

Modern synthetic pathways towards eribulin and its subunits

• Sebastian Dominik Graf

Beilstein J. Org. Chem. 2026, 22, 495–526, doi:10.3762/bjoc.22.37

• challenging soft tissue sarcoma, 1 has shown promise in prolonging overall survival and improving quality of life. The key feature that underpins 1's clinical importance is its unique mechanism of action [41][42][43][44][45][46][47][48][49][50]. Unlike other microtubule inhibitors such as taxanes and vinca

Synthesis of a HDAC inhibitor–nanogold probe for cryo-EM visualization in class I HDAC co-repressor complexes

• Wiktoria A. Pytel,
• John W. R. Schwabe and
• James T. Hodgkinson

Beilstein J. Org. Chem. 2026, 22, 480–485, doi:10.3762/bjoc.22.35

• independently and that their activities and modulation by inhibitors and activators are closely coupled. Both enzymes exist in at least two distinguishable states that differ in their kinetic properties, consistent with the two distinct structural states of the complex observed in the cryo-EM maps [10]. However

• , like other benzamide HDAC inhibitors, exhibits slow on/off binding kinetics, hence once bound to the HDAC within the complex it should not readily dissociate [16]. A crystal structure of HDAC2 bound to an analogue of CI-994 (PDB: 4LY1) revealed that the acetamide moiety is oriented outside the HDAC

• -labeled HDAC inhibitors could serve as effective fiducial markers in cryo-EM, facilitating the localization of distinct subunits or binding sites within large and flexible multiprotein complexes. HDAC1–3 inhibitor CI-994; HDAC inhibitor–nanogold probe Au–(CI-994); structure of amine-functionalized 1.4 nm

Structural reassignment of compound 968, an allosteric glutaminase inhibitor

• Lindsey A. Albertelli,
• Sainabou Jallow,
• Chun Li and
• Scott M. Ulrich

Beilstein J. Org. Chem. 2026, 22, 455–460, doi:10.3762/bjoc.22.33

• demands of the proliferative state creates an opportunity to selectively target cancer cells [1][7]. Chemical inhibition of GLS has emerged as an attractive anticancer strategy, and several classes of GLS inhibitors have been discovered [1][2]. DON is a diazo-containing electrophilic glutamine analog that

• glutaminase inhibition on several cancer cell lines (Figure 1) [15][16]. The anticancer effects of compound 968 have been tested in combination with other drugs such as paclitaxel [17], erlotinib [18], apigenin [19], metformin [20], and inhibitors of tissue transglutaminase [21]. Compound 968 was recently

• found to suppress the growth of a luminal breast cancer cell line that expresses GLS2 and is insensitive to GLS1-specific inhibitors such as BPTES and CB-839 [22]. After initiating a project to synthesize derivatives of compound 968, we searched the literature for synthetic routes towards its scaffold

Synthesis and anti-cancer activity of naphthalimide–organylselanyl conjugates

• Rajkumar Ravi and
• Selvakumar Karuthapandi

Beilstein J. Org. Chem. 2026, 22, 416–435, doi:10.3762/bjoc.22.29

• strategies for TNBC are often inadequate, with limited effectiveness for many patients, underscoring the urgent need for novel treatment approaches. In particular, the development of new small-molecule EGFR tyrosine kinase inhibitors holds significant promise, as there is currently no highly effective

• , many of which exhibit promising applications in medicinal chemistry [18][19]. Selenium has been incorporated into non-steroidal anti-inflammatory drugs (NSAIDs) and histone deacetylase (HDAC) inhibitors, both of which show considerable potential in anticancer therapy [20][21]. Over the last few decades

Spirobarbiturates with a pyrrolizidine moiety: synthesis, structure and biological evaluation

• Arthur A. Puzyrkov,
• Andrew S. Drachuk,
• Ekaterina A. Popova,
• Alexander V. Stepakov and
• Vitali M. Boitsov

Beilstein J. Org. Chem. 2026, 22, 274–288, doi:10.3762/bjoc.22.20

• ] and antiviral activities (7,7a-diepialexine) [40]. Some pyrrolizidine derivatives are inhibitors of enzymes such as acetylcholinesterase (AChE) (echimidine) [41] or β-N-acetylglucosaminidase (GlcNAcases) (pochonicine) [42]. Our previous studies have shown that spiro-fused barbiturates containing

A mild and atom-efficient four-component cascade strategy for the construction of biologically relevant 4-hydroxyquinolin-2(1H)-one derivatives

• Dmitrii A. Grishin,
• Kseniia I. Sharkovskaia,
• Ilya G. Kolmakov,
• Daria A. Ipatova,
• Rostislav A. Petrov,
• Nikolai D. Dagaev,
• Dmitry A. Skvortsov,
• Maria G. Khrenova,
• Valeriy V. Andreychev,
• Sergei A. Evteev,
• Yan A. Ivanenkov,
• Roman L. Antipin,
• Olga А. Dontsova and
• Elena K. Beloglazkina

Beilstein J. Org. Chem. 2026, 22, 244–256, doi:10.3762/bjoc.22.18

• , and 13a inhibited the growth of the E. coli ΔtolC strain while exhibiting minimal cytotoxicity toward human cell lines, even at concentrations up to 100 μmol/L. Their cytotoxicity profile differs markedly from that of known topoisomerase II inhibitors. Although the synthesized compounds did not

Competitive cyclization of ethyl trifluoroacetoacetate and methyl ketones with 1,3-diamino-2-propanol into hydrogenated oxazolo- and pyrimido-condensed pyridones

• Svetlana O. Kushch,
• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess,
• Pavel A. Slepukhin,
• Alexandrina S. Volobueva,
• Vladimir V. Zarubaev and
• Victor I. Saloutin

Beilstein J. Org. Chem. 2025, 21, 2716–2729, doi:10.3762/bjoc.21.209

• antileishmanial [47], antibacterial [48], antimalarial agents [49] as well as COX-2 [50] and FGFR [51] inhibitors found among them. Moreover, various drugs (antipsychotic risperidone [52] and pirenperone [53], antiallergic ramastine [54]) have been obtained on the basis of pyrido[1,2-a]pyrimidine; and

Thiazolidinones: novel insights from microwave synthesis, computational studies, and potentially bioactive hybrids

• Luan A. Martinho,
• Victor H. J. G. Praciano,
• Guilherme D. R. Matos,
• Claudia C. Gatto and
• Carlos Kleber Z. Andrade

Beilstein J. Org. Chem. 2025, 21, 2618–2636, doi:10.3762/bjoc.21.203

• ]. Some rhodanine-based derivatives act as inhibitors of hepatitis C virus (HCV) protease [19], UDP-N-acetylmuramate/ʟ-alanine ligase [20], histidine decarboxylase [21], aldose/aldehyde reductase [22], fungal protein mannosyl transferase 1 (PMT1) [23], metallo β-lactamase [24], cathepsin D [25], JNK

Synthesis and characterization of a isothiouronium-calix[4]arene derivative: self-assembly and anticancer activity

• Giuseppe Granata,
• Loredana Ferreri,
• Claudia Giovanna Leotta,
• Giovanni Mario Pitari and
• Grazia Maria Letizia Consoli

Beilstein J. Org. Chem. 2025, 21, 2535–2541, doi:10.3762/bjoc.21.195

• class of interest in the search for new chemotherapeutic agents. They are known inhibitors of protein kinase C [40] and agonists of the GABA-type [41] and histamine-H3 receptors [42]. S-Allylic isothiouronium salts substituted with aliphatic groups have shown to combine high antitumor activity against

Synthetic study toward vibralactone

• Liang Shi,
• Jiayi Song,
• Yiqing Li,
• Jia-Chen Li,
• Shuqi Li,
• Li Ren,
• Zhi-Yun Liu and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2025, 21, 2376–2382, doi:10.3762/bjoc.21.182

• several potent pancreatic lipase inhibitors with nanomolar IC50 values [24], further supporting vibralactone as a promising lead compound warranting further investigation. Although vibralactone (6) is a relatively small natural product, its molecular structure features a unique 4/5-fused bicyclic β

Comparative analysis of complanadine A total syntheses

• Reem Al-Ahmad and
• Mingji Dai

Beilstein J. Org. Chem. 2025, 21, 2334–2344, doi:10.3762/bjoc.21.178

• molecules such as the huperzines have been discovered and advanced into human clinical trials as acetylcholinesterase inhibitors for treating Alzheimer’s disease [3]. Among the lycopodium family, complanadine A (1, Scheme 1) and its natural congeners such as complanadines B (2), D (3), and E (4) were

Research towards selective inhibition of the CLK3 kinase

• Vinay Kumar Singh,
• Frédéric Justaud,
• Dabbugoddu Brahmaiah,
• Nangunoori Sampath Kumar,
• Blandine Baratte,
• Thomas Robert,
• Stéphane Bach,
• Chada Raji Reddy,
• Nicolas Levoin and
• René L. Grée

Beilstein J. Org. Chem. 2025, 21, 2250–2259, doi:10.3762/bjoc.21.172

• , as an attractive residue to design inhibitors with increased affinity towards this kinase as compared to the three other isoforms CLK1, CLK2, and CLK4. Based on this observation, we have been able to transform a molecule (DB18) previously established with a very low activity on CLK3 into a derivative

• as overexpression, is implicated in the pathogenesis of numerous deleterious diseases including nervous and inflammatory disorders as well as a number of malignancies [1][2][3]. Kinases are also known to be highly druggable by both allosteric and competitive inhibitors. As a consequence, protein

• kinases have become one of the most important drug targets: between a quarter to a third of the drug discovery efforts worldwide are focused on the discovery of new protein kinase inhibitors. More than 80 FDA-approved drugs that target about two dozen different protein kinases were discovered during the

Synthesis of triazolo- and tetrazolo-fused 1,4-benzodiazepines via one-pot Ugi–azide and Cu-free click reactions

• Xiaoming Ma,
• Zijie Gao,
• Jiawei Niu,
• Wentao Shao,
• Shenghu Yan,
• Sai Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 2202–2210, doi:10.3762/bjoc.21.167

• ][2][3][4][5]. For example, triazole-fused 1,4-benzodiazepins are protease inhibitors [6] and part of drug molecules such as alprazolam [7], estazolam [8], and triazolam [9] (Figure 1). Tetrazole-containing functional materials have been developed as photographic sensitizers, diagnostic contrast

Research progress on calixarene/pillararene-based controlled drug release systems

• Liu-Huan Yi,
• Jian Qin,
• Si-Ran Lu,
• Liu-Pan Yang,
• Li-Li Wang and
• Huan Yao

Beilstein J. Org. Chem. 2025, 21, 1757–1785, doi:10.3762/bjoc.21.139

• converts myristoylcholine into myristic acid and choline [120]. SC4A binds to the non-amphiphilic choline but not to the amphiphilic myristic acid, leading to the disassembly of the composite vesicles. Currently, the clinical treatment of Alzheimer's disease is mainly based on cholinesterase inhibitors

Approaches to stereoselective 1,1'-glycosylation

• Daniele Zucchetta and
• Alla Zamyatina

Beilstein J. Org. Chem. 2025, 21, 1700–1718, doi:10.3762/bjoc.21.133

• , the chemical synthesis of thiotrehalose analogs [116][117] provides a versatile tool for the construction of therapeutically relevant ligands or inhibitors of carbohydrate-specific innate immune receptors. Synthetic thiodigalactosides and their derivatives have been identified as selective inhibitors

A multicomponent reaction-initiated synthesis of imidazopyridine-fused isoquinolinones

• Ashutosh Nath,
• John Mark Awad and
• Wei Zhang

Beilstein J. Org. Chem. 2025, 21, 1161–1169, doi:10.3762/bjoc.21.92

• as HIV inhibitors [14]. The imidazo[1,2-a]pyridine ring can be readily synthesized by the GBB reaction [10][15], while the isoquinolinone ring is commonly generated by a cyclative lactamization process. Performing a GBB reaction followed by an intramolecular amidation is a good approach for making

A versatile route towards 6-arylpipecolic acids

• Erich Gebel,
• Cornelia Göcke,
• Carolin Gruner and
• Norbert Sewald

Beilstein J. Org. Chem. 2025, 21, 1104–1115, doi:10.3762/bjoc.21.88

• important role as building blocks for peptide synthesis [1][2][3][4][5], as organocatalysts [6][7][8][9][10] and as enzyme inhibitors [4][11][12][13]. The incorporation of such amino acids into peptides can, for example, influence peptide conformation, the binding affinity to receptors [14], as well as

Silver(I) triflate-catalyzed post-Ugi synthesis of pyrazolodiazepines

• Muhammad Hasan,
• Anatoly A. Peshkov,
• Syed Anis Ali Shah,
• Andrey Belyaev,
• Chang-Keun Lim,
• Shunyi Wang and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2025, 21, 915–925, doi:10.3762/bjoc.21.74

• anesthesia [14]. The imidazo[4,5-d][1,3]diazepine core is present in pentostatin and coformycin, which are naturally occurring N-nucleoside inhibitors of adenosine deaminase, known for their antibiotic and anticancer properties [15][16][17]. These examples highlight the importance of developing novel

4-(1-Methylamino)ethylidene-1,5-disubstituted pyrrolidine-2,3-diones: synthesis, anti-inflammatory effect and in silico approaches

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Luc Van Meervelt,
• Do Thi Thao and
• Nguyen Minh Thong

Beilstein J. Org. Chem. 2025, 21, 817–829, doi:10.3762/bjoc.21.65

• Table 3 indicate that none of the candidates acted as substrates or inhibitors of CYP2D6, even though all were substrates for CYP3A4, suggesting potential metabolism via this pathway without any inhibitory effects. Excretion was assessed by examining total clearance, which is considered high when the

Orthogonal photoswitching of heterobivalent azobenzene glycoclusters: the effect of glycoligand orientation in bacterial adhesion

• Leon M. Friedrich and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2025, 21, 736–748, doi:10.3762/bjoc.21.57

• –inhibition assay. The measured results were systematically contextualized employing new reference compounds such as the respective homobivalent Man/Man glycocluster. An in-depth study comprising the analysis of the photochromic properties and the potential as inhibitors of bacterial adhesion of the synthetic

• UV–vis spectra of the two photoswitchable units. This design laid the basis for a robust switching cycle comprising the EManEGlc, the EManZGlc, and the ZManZGlc isomer of 1 [24]. In this contribution, we address the question of how the different isomers of 1 perform as inhibitors of bacterial

• potency as inhibitors of Man-specific bacterial adhesion investigated. Results and Discussion Synthesis For the preparation of the homobivalent glycocluster 6αMan3αMan 2, the known mannosyl thioacetate 7 [31] was prepared from the trichloroacetimidate 6 [32] and thioacetic acid in an α-selective reaction