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

• receptor agonists). In other cases, however, challenging medicinal chemistry is required to achieve clinical efficacy, as exemplified by the complex development of the heavily modified tricyclic peptide MK-0616, a PCSK9 inhibitor in phase III clinical trials that was originally derived from an mRNA display

• drugs derived from native peptide substrates. A classic example is the ACE inhibitor captopril, an analogue of a snake venom peptide, the development of which has been cited as an early success story for structure-based rational drug design [12][13]. Despite the long history, there is still no

• straightforward and generalisable workflow with a reasonable success rate for achieving the transformation from peptide to small molecule inhibitor. With the rapid maturation of computational tools based on artificial intelligence (AI), this Perspective highlights selected nascent examples where AI has been used

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

• other non-enzymatic proteins [7] are essentially undruggable using conventional inhibitor-based approaches [4][8]. Consequently, protein–protein interaction (PPI)-based targeted protein degradation (TPD) strategies have attracted increasing attention over the past two decades [9][10]. Among them

• often exist in cancer and nervous system diseases [47]. Palbociclib was the first small-molecule inhibitor approved by the FDA in 2015 to target CDK4/6 in the CDK family [48]. Soon after, ribociclib and abemaciclib, small-molecule inhibitors targeting CDK4/6, were also approved by the FDA for breast

• pharmaceutical chemists. In 2019, Gray, Zhang and co-workers designed a PROTAC-1 (1) to degrade CDK4/6 [21]. To construct compound 1 they used the CDK4/6 inhibitor palbociclib as the POI ligand, pomalidomide, which combines with CRBN as the E3 ligand and a 4-carbon alkyl linker to connect them. The compound can

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

• adjacent to the ATP-binding site of CK2α [5][6]. Fragment-based ligand discovery subsequently enabled the development of CAM4066, a selective inhibitor that simultaneously engages the αD and ATP sites. CAM4066 validated the αD region as a tractable and selective binding pocket for CK2 kinase inhibition

• ]. This event-driven mode of action enables catalytic turnover, can reduce off-target toxicities associated with high inhibitor doses, and does not require a deep or well-defined binding pocket, allowing potential access to targets considered “undruggable” by conventional small molecules [8]. In 2018, a

• PROTAC targeting CK2 was reported in the literature. This used CX-4945, a potent CK2 inhibitor, as the CK2 warhead [9][10]. However, as CX-4945 targeted the ATP-binding site of CK2, it also displayed nanomolar affinity for the ATP-binding sites of other kinases, like CLK2 [11]. Therefore, finding a

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

• FGFR2-selective inhibitor, is the first highly selective FGFR2 inhibitor. Although substantial advancements have been made in developing FGFR2-targeted therapeutics, the sustained clinical efficacy of these inhibitors in oncology remains constrained by the emergence of acquired resistance mechanisms

• purpose the clinically validated inhibitor erdafitinib as a POI binder that selectively targets FGFR2. Based on the analysis of the co-crystal structure of erdafitinib bound to the FGFR kinase domain (PDB: 5EW8, https://doi.org/10.2210/pdb5EW8/pdb) [30], we observed that the aliphatic amine group is

• subtype selectivity and the ability to degrade membrane-bound FGFR2. This molecule successfully repurposed erdafitinib, a broad-spectrum FGFR inhibitor, into a highly selective degrader. It not only provides a new chemical tool for investigating FGFR2 function but also lays a crucial foundation for the

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

• inhibitor of the survivin–histone H3 tail interaction would be a very valuable chemical tool because it could allow to deliberately shut down the recruitment of the CPC to the nucleosomes and to study its effect on CPC function. Results and Discussion In 2005, our group discovered molecular tweezers with

• –protein interaction (PPI) recruits the CPC to the kinetochore which hinges on its histone H3 peptide binding with its N-terminal sequence to the BIR domain of survivin. The biological affinity of this interaction (Kd ≈ 1 µM) is not sufficient as anchor point for an inhibitor; therefore a molecular tweezer

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

• , Halaven) due to its unique mechanism of action as a microtubule dynamics inhibitor. It is primarily used in the treatment of metastatic breast cancer and liposarcoma, offering a new therapeutic option for patients with advanced disease. To meet the increasing clinical demand, the research on new synthetic

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

• LE1 7RH, UK 10.3762/bjoc.22.35 Abstract Class I histone deacetylases (HDACs 1–3) serve as catalytic subunits within seven multiprotein co-repressor complexes, each of which has distinct functions in the cell. We report the synthesis of a HDAC inhibitor–nanogold probe, derived from the class I HDAC

• inhibitor CI-994, for cryo-electron microscopy (cryo-EM) visualization of the HDAC catalytic domain within class I HDAC co-repressor complexes. The nanogold probe retained HDAC inhibitory activity comparable to CI-994 against the HDAC1-LSD1-CoREST complex in vitro. In cryo-EM studies, 2D class averages

• synthesize a nanogold-conjugated HDAC inhibitor and evaluate its applicability in single-particle cryo-EM to unambiguously determine the positioning and orientation of the HDAC active site within the CoREST complex. Results and Discussion Design and synthesis of a HDAC inhibitor–nanogold probe For the basis

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

• anticancer drug target. Compound 968 is a glutaminase inhibitor that is widely used to probe cancer cells’ dependence on glutaminase activity. Here, we show by NMR spectroscopy and X-ray crystallography that the reported benzo[c]phenanthridine structure of compound 968 is incorrect; its true structure is the

• inhibits glutaminase by covalently labeling the catalytic serine [8]. DON inhibits other glutamine-utilizing enzymes such as asparagine synthetase and has activity against a wide range of cancer cell lines [9][10]. BPTES is a potent allosteric inhibitor of GAC/KGA that binds at the dimer–dimer interface

• class of glutaminase inhibitor discovered in a screen for compounds able to revert the transformed phenotype of cells harboring oncogenic Dbl, the nucleotide exchange factor of the small GTPase Rho [14]. Compound 968 is a dual GLS1/GLS2 inhibitor and has found wide use to probe the effects of

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

• , respectively, and the molecular docking simulations revealed that compounds 7 and 8 fit well within the active (1M17) and inactive (4HJO) binding pockets of the epidermal growth factor receptor (EGFR) tyrosine kinase. Their binding modes were consistent with that of the co-crystallised inhibitor erlotinib

Ring contraction and ring expansion reactions in terpenoid biosynthesis and their application to total synthesis

• Nicolas Kratena,
• Nicolas Heinzig and
• Peter Gärtner

Beilstein J. Org. Chem. 2026, 22, 289–343, doi:10.3762/bjoc.22.21

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

• well-known topoisomerase II inhibitor doxorubicin (see Supporting Information File 1, page S52), whose toxicity correlates with the cell proliferation rate. Compounds 13b and 13c exhibited non-specific toxicity across all tested cell lines. Antibacterial activities of compounds 9–14 were evaluated in

Conformational analysis of difluoromethylornithine: factors influencing its gas-phase and bioactive conformations

• Matheus P. Freitas

Beilstein J. Org. Chem. 2026, 22, 237–243, doi:10.3762/bjoc.22.17

• Matheus P. Freitas Department of Chemistry, Institute of Natural Sciences, Federal University of Lavras, 37200-900, Lavras, MG, Brazil 10.3762/bjoc.22.17 Abstract Difluoromethylornithine (DFMO, eflornithine) is a fluorinated analogue of ornithine that serves both as an inhibitor of ornithine

• as a potent inhibitor of ornithine decarboxylase, the key enzyme that catalyzes the first step in polyamine biosynthesis [6]. This inhibition underlies both its therapeutic utility and its importance as a biochemical probe. From a structural standpoint, DFMO provides an intriguing case study for

Total synthesis of natural products based on hydrogenation of aromatic rings

• Haoxiang Wu and
• Xiangbing Qi

Beilstein J. Org. Chem. 2026, 22, 88–122, doi:10.3762/bjoc.22.4

• (±)-serralongamine A. With (±)-serralongamine A in hand, huperzine N and N-epi-huperzine N could be obtained via a reduction–oxidation sequence [91] (Scheme 21). Asymmetric synthesis towards indenopiperidine core of an 11-β-HSD-1 inhibitor, 2016 Growing interest has focused on inhibiting 11-β-hydroxysteroid

• dehydrogenase type 1 (11-β-HSD-1), a key enzyme that alleviates insulin resistance by lowering cortisol production. Compound 157 emerged as a promising 11-β-HSD-1 inhibitor candidate. In 2016, researchers from Boehringer Ingelheim Pharmaceuticals and the University of Pennsylvania reported a concise and

Synthesis and applications of alkenyl chlorides (vinyl chlorides): a review

• Daniel S. Müller

Beilstein J. Org. Chem. 2026, 22, 1–63, doi:10.3762/bjoc.22.1

• HIV-1 non-nucleoside reverse transcriptase inhibitor, they aimed to improve the preparation of compound 19, whose yield had previously been limited to 22% following a similar route. They noticed that in situ-generated species such as POCl3 or HCl triggered ring opening of dichloride 15 to produce a

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

• inhibitor doravirine [31], calcitonin gene-related peptide (CGRP) antagonist ubrogepant [32], dipeptidyl peptidase-4 (DPP-4) inhibitor gemigliptin [33]. The trifluoromethyl pyridine framework is also widely used in the development of plant protection products [34], including the fungicides fluopicolide [35

Synthesis of new tetra- and pentacyclic, methylenedioxy- and ethylenedioxy-substituted derivatives of the dibenzo[c,f][1,2]thiazepine ring system

• Gábor Berecz,
• András Dancsó,
• Mária Tóthné Lauritz,
• Loránd Kiss,
• Gyula Simig and
• Balázs Volk

Beilstein J. Org. Chem. 2025, 21, 2645–2656, doi:10.3762/bjoc.21.205

• compounds are of interest, e.g., the marketed drugs eliglustat for the treatment of Gaucher’s disease [13][14] and the antihypertensive agent proroxan [15][16]. Licogliflozin is a sodium-glucose transporter 2 inhibitor developed in several indications: obesity [17], polycystic ovary syndrome [18], and non

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

• vibralactone, a potent inhibitor of pancreatic lipase, is reported. The synthesis of the challenging all-carbon quaternary center within the cyclopentene ring was achieved through intramolecular alkylidene carbene C–H insertion. Keywords: alkylidene carbene; C–H insertion; total synthesis; vibralactone

• moiety have been isolated and demonstrate potent bioactivities [7] (Figure 1). For example, lactacystin (1) which was isolated by Ōmura and co-workers [8][9], is a potent and selective proteasome inhibitor; its active form is the synthetic precursor omuralide (2) [10][11]. Similarly, salinosporamide (3

• ), a marine natural product isolated by Fenical and co-workers [12], also acts as a proteasome inhibitor and displays more potent in vitro cytotoxicity than omuralide (2). Anisatin (4), which contains a characteristic spiro β-lactone has been identified as a noncompetitive antagonist of GABA-gated ion

Recent advances in Norrish–Yang cyclization and dicarbonyl photoredox reactions for natural product synthesis

• Peng-Xi Luo,
• Jin-Xuan Yang,
• Shao-Min Fu and
• Bo Liu

Beilstein J. Org. Chem. 2025, 21, 2315–2333, doi:10.3762/bjoc.21.177

• inhibitor [53][54]. In 2018, Suzuki’s group employed their developed photoredox reaction to carry out a model study on the chiral [5,6]-spiroketal core of γ-rubromycin [50]. 1,2-Naphthoquinone 106 was selected as the model substrate for the photoredox reaction (Scheme 13a). Lawsone (101) underwent reductive

Halogenated butyrolactones from the biomass-derived synthon levoglucosenone

• Johannes Puschnig,
• Martyn Jevric and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2025, 21, 2297–2301, doi:10.3762/bjoc.21.175

• reduced form 6, which is sold as a solvent, is an inexpensive commercially available reagent (Scheme 1) [21]. Monohalogenation of LGO giving chloride 7a [22] and bromide 7b [23] is readily achieved in a single step, however, fluorinated 7c, which is a potent inflammasone inhibitor (0.8 ± 0.5 µM), has only

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

• , Khudwadhar, Gulaothi, Bulandshahr, Uttar Pradesh-203408, India Chemveda Life Sciences India Pvt. Ltd., B-11/1, IDA Uppal, Hyderabad-500039, Telangana, India Sorbonne Université, CNRS, FR 2424, Plateforme de criblage KISSf (Kinase Inhibitor Specialized Screening facility), Station Biologique de Roscoff, CS

• splicing process. Among the four isoforms of CLKs, CLK3 is the one for which the biological roles are less understood, in part because no selective inhibitor of this challenging kinase has been found to date. Based on structural analysis of the CLKs we have identified the lysine 241, present only in CLK3

• VS-77 which has now a significant affinity toward CLK3 (IC50 = 0.3 μM). Thus, VS-77 appears as a new pan-inhibitor of the CLK family. Keywords: cancer; CLK3; kinases; molecular modelling; quinazolines; triazoles; Introduction Human protein kinases are a family comprising nearly 535

Electrochemical cyclization of alkynes to construct five-membered nitrogen-heterocyclic rings

• Lifen Peng,
• Ting Wang,
• Zhiwen Yuan,
• Bin Li,
• Zilong Tang,
• Xirong Liu,
• Hui Li,
• Guofang Jiang,
• Chunling Zeng,
• Henry N. C. Wong and
• Xiao-Shui Peng

Beilstein J. Org. Chem. 2025, 21, 2173–2201, doi:10.3762/bjoc.21.166

• used as an inhibitor of cyclin dependent kinase (CDK8) [31]. Sulfonamide-N-benzoxaborole analog GSK8175 is an inhibitor against hepatitis C virus (HCV) [20] (Figure 1). The construction of five-membered rings obtained growing attention [32][33][34][35][36][37][38], and alkynes [39][40][41][42][43][44

C2 to C6 biobased carbonyl platforms for fine chemistry

• Jingjing Jiang,
• Muhammad Noman Haider Tariq,
• Florence Popowycz,
• Yanlong Gu and
• Yves Queneau

Beilstein J. Org. Chem. 2025, 21, 2103–2172, doi:10.3762/bjoc.21.165

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

• and enhanced the overall solubility and biocompatibility of the azo-calixarene structure, designing it as a drug carrier (Figure 18) [126]. This carrier binds to the ferroptosis inhibitor liproxstatin-1 (Lip) and releases it selectively in hypoxic environments. This mechanism aims to counteract the

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

• , respectively [64]. The use of TMS-stabilized lactol acceptors also found application in the synthesis of an E-selectin inhibitor. The tribenzylated TMS-β-galactose acceptor 56 was reacted with the tetrabenzylated mannosyl fluoride donor 55, ensuring high stereoselectivity in the formation of the α,β-1,1

• '-conjugated product 57, a precursor of the E-selectin inhibitor (Scheme 5) [39][40]. However, when the benzyl protecting groups were replaced with acetyl groups, as in the case of the tetraacetylated Gal-derived acceptor 58, the anomeric hydroxy group could only be partially trapped in the β-configuration (α

Highly distinguishable isomeric states of a tripodal arylazopyrazole derivative on graphite through electron/hole-induced switching at ambient conditions

• Himani Malik,
• Sudha Devi,
• Debapriya Gupta,
• Ankit Kumar Gaur,
• Sugumar Venkataramani and
• Thiruvancheril G. Gopakumar

Beilstein J. Org. Chem. 2025, 21, 1496–1507, doi:10.3762/bjoc.21.112

• imparted quantitative and reversible photoswitching [20][21]. The long-term photoswitching stability and tunable half-lifes of Z isomers of azopyrazole-based switches [20][21][22] have made their way to several applications in thermal energy storage [23], photoswitchable inhibitor [24], photoswitchable