Herbert Waldmann

Emeritus Direktor, Chemische Biologie

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Research Concept

Research in the Department of Chemical Biology is focused on the modulation and analysis of complex biological processes with approaches originating from chemistry. To this end, we have developed and employed methods for chem- and bioinformatic charting of biologically relevant chemical space, invented novel design principles and strategies for the synthesis of natural product-inspired compound collections and evaluate them in the study of biological phenomena. We employ target- and cell-based screening to find modulators of cellular processes and identify their biological targets. .

In general, the major research focus of the De-partment is on the identification of new biologically relevant compound classes, the development of methodology for their synthesis, in particular natu-ral product-inspired compound collections and their use in the study of biological processes. We have established a state-of-the-art screening platform, target-, cell-based and phenotypic screens and the methodology to identify the cellular targets of bioactive small molecules. The Compound Management and Screening Center (COMAS) hosts a ca. 250,000-member compound library, including ca. 15,000 proprietary in-house synthesized natural product-inspired compounds. Screening at COMAS enables access to various areas of biology, e.g. Hedgehog signaling, autophagy and unbiased bio-logical compound characterization in multipara-metric high-content morphological profiling, e.g. in the Cell Painting assay. 

The Chemical Genomics Centre (CGC) of the Max Planck Society (MPS) established by the Department is considered a role model for successful aca-demia/industry collaboration. The third 5-year phase of CGC hosted four Research Groups funded jointly by Merck, AstraZeneca, Pfizer and the MPS and concluded its activities in December 2024. The Department’s natural product-inspired synthe-sis and cellular target identification program has led to the establishment of the collaborative RIKEN-Max Planck Joint Research Center for Systems Chemical Biology. This large-scale cooperation concluded its joint research program in March 2022.

Natural product (NP) scaffolds represent the bio-logically relevant and pre-validated regions of chemical structure space explored by nature, and provide evolutionarily selected starting points for compound collection design. 
We developed a novel design principle for NP-inspired compound collections which combines evolutionary selection, with rapid exploration of biologically relevant chemical space through frag-ment-based compound design. Unprecedented combinations and fusions of NP fragments yield novel scaffolds that retain the chemical and biolog-ical characteristics of NPs, yet extend beyond the biologically relevant chemical space explored by nature (Fig. 1). These ‘pseudo-natural products’ are not accessible through biosynthesis. Compound collections based on such molecular scaffolds may have different properties compared to NPs, and may display unprecedented biological activities. In fact, the workflow of pseudo-natural product design, synthesis and biological analysis is comparable to the concept to natural evolution such that pseudo-natural products can be regarded as the human-made equivalent, i.e. a chemical evolution of natural product structure.[1,2]

For the preparation of pseudo-natural product libraries we have developed novel synthetic chem-istries that enable complexity-generating de novo fusion of ring systems in patterns unprecedented in nature, ideally combining ring systems that are normally not found together. 

Following this design principle, we combined the scaffolds of indole- and tropane alkaloids to yield indotropanes [3], by harnessing a Cu(I)-catalysed enantioselective intermolecular 1,3-dipolar cy-cloaddition, and combination of the indole- and the morphine fragment delivered indomorphans.[4] More than two fragments can be linked, for instance by combining pyrrolidine-, pyrroline- and succin-imide-NP scaffolds [5], or as shown for pyrano-furo-pyridones by combining 2-pyridone and (dihy-dro)pyran fragments, by means of Pd-catalysed Tsuji–Trost annulation cascades.[6] A 155-mem-bered chemically and biologically diverse pyrroquin-oline pseudo-NP collection was generated from a few repeatedly used tetrahydro-quinoline- and pyr-rolidine fragments in eight different molecular con-nectivities and regioisomeric arrangements. A unify-ing synthetic approach harnessing Ag-catalysed 1,3-dipolar cycloadditions of azomethine ylides with electron deficient alkenes and delivered the pyrro-quinoline scaffolds via Povarov-type dimerisation of enamines.[7] 

Highly NP-prevalent indole or chromanone ring systems were combined in unprecedented fusions with readily accessible NP-fragments derived from commercially available Cinchona alkaloids quinine and quinidine as well as NPs griseofulvin and si-nomenine. A range of annulation reactions, includ-ing edge-fusion by indolisations and spiro-fusions by either oxa-Pictet–Spengler reactions or Kabbe condensations yielded a library of 244 chemically and biologically diverse compounds with varying ring combinations, connectivities, stereo- and regi-oisomeric fragment arrangements.[8] Combination of the indole-containing 4H-pyra-noindole fragment and the fragment-sized NP grise-ofulin yielded indofulvins through an iso-oxa-Pictet-Spengler reaction as the key step to combine the two fragments with a fusion spiro-connection pat-tern.[9] Indofulvins are novel inhibitors of starva-tion-induced autophagy via modulation of mito-chondrial function. The pyrroquinoline PNP osteo-genesis inhibitors tafbromin selectively targets the bromodomain 2 of the epigenetic TAF1 protein.[10] In a successful combination of the PNP principle with the complexity-to-diversity ring distortion ap-proach, fragment-sized α-methylene-sesquiterpene lactone scaffolds, were combined with alkaloid-de-rived pyrrolidine fragments to yield chemically and biologically diverse pseudo-sesquiterpenoid alka-loids.[11] Extension of the PNP principle led to the diverse pseudo-natural product (PNP) strategy which combines biological relevance of PNPs with diversity-oriented synthesis (DOS). A common diver-gent intermediate was converted through indole dearomatization methodologies to afford diverse three-dimensional molecular frameworks that could be further diversified to eight different PNP clas-ses.[12]  

Unprecedented combination of monoterpene indole alkaloid (MIA) fragments yielded pseudo-NPs that reside in a unique area of chemical space with high spatial complexity-density shared with MIAs but only sparsely populated by other natural products and drugs.[13] 

Cheminformatic analysis of the synthesized pseudo-NP classes showed that the majority are fairly “drug like”, may have advantageous properties for molec-ular discovery and that their natural product like-ness score resembles the score of drugs. Analysis of the ChEMBL database which hosts ca. 2.1 mio com-pounds assigned with bioactivity revealed that nu-merous PNPs (ca. 690,000, i.e. 32%) have been pre-pared during the last 40 years, probably fuelled by intuitive reasoning, and that the relative proportion of PNPs has increased steadily during this time.[14, 15] Similarly, analysis of the highly sourced Enamine library of commercially available compounds re-vealed that of the ca. 3.5 mio compounds available from this vendor ca. 1.1 mio (i.e. 32%) are PNPs. Hence, a multitude of PNPs is readily available com-mercially.[15]

Analysis of >3,000 compounds in clinical phases 1-3 and on the market, acting on >2000 targets gratify-ingly revealed a consistent increase of PNPs in real world drugs over time, with a sharp step-up from 1990 onwards. The fraction of PNPs in drugs dou-bled every 2-3 decades, and in the 2010 decade 67%of all clinical compounds were PNPs.[16] Post 2008 the overall clinical compound is 54% more likely a PNP, which is true for 14 out of 17 major target clas-ses. Only ca. 11% of the NP-fragments identified oc-cur in clinical compounds and less than 100 frag-ments account for ca. 90% of total NP fragment oc-currence in drugs. Thus, there is a large pool of un-der-used fragments, and a vast number of novel combinations available from commercial screening libraries and as building blocks. 

These findings validate the PNP principle as a histor-ically successful and proven approach to the discov-ery of novel bioactive chemical matter in general, and real-world drugs in particular. 

 

For identification and validation of the cellular tar-gets and the modes of action of the pseudo-NPs a suite of methods was employed, including quantita-tive proteomics, computational approaches, bio-chemical, biophysical, genetic, molecular, and cell-biological techniques. Examples are shown in Fig. 2. 
In “Cell Painting” the cellular phenotype is charac-terized by selective staining of intracellular struc-tures and automated microscope readout of small molecule-induced perturbations. Changes in hun-dreds of parameters yield characteristic fingerprints that are compared with fingerprints recorded for annotated reference compounds to detect mode of action, and provide guidance if established target-ID methods fail. For instance, Cell Painting revealed that the autophagy inhibiting autoquins (for which we could not identify a putative target by means of proteomics or target prediction) are lysosomotropic agents.[17] They raise the pH and sequester Fe2+ into the lysosome leading to increased ROS produc-tion and subsequent impaired autophagosome-ly-sosome fusion.[17] It also allowed to qualitatively assess different biological potency and diversity of PNP classes in general,[7,8] as well as qualitative structure-activity correlation, thereby guiding li-brary design.[6] Even direct target identification can be achieved.[18] 
Cell Painting enabled unbiased identification of bio-activity in particular in combination with other tar-get-ID methods. For instance, combination of the method with thermal proteome profiling revealed a novel ligand of the sigma1 receptor [19], and target-independent impairment of cholesterol homeosta-sis by chemically different lysosome-targeting com-pounds.[3]

For wider coverage of NP-inspired chemical and bi-ological space, the PNP principle was combined with macrocycle formation. Synthesis of dimeric PNP-macrocycles derived from cinchona alkaloids led to the discovery of tantalosin, the first inhibitor of the IST1-CHMP1B interaction. Tantalosin impairs endo-somal recycling and induces noncanonical LC3 lipi-dation.[20,21] Macrocyclic PNPs termed “PepNats” incorporate conformation-determining NP frag-ments into a peptidic macrocycle [22]. We identified novel and potent PepNat ligands of the SPSB2 pro-tein that binds to inducible nitric oxide synthase (iNOS), and selective ligands for AGRP-binding mel-anocortin (MC) receptors. 

Pseudo-NPs that induce degradation of indoleam-ine-2,3-dioxygenase 1 (IDO1) through recruitment of an E3-ligase (“molecular glues”) were identified in a cell-based assay monitoring immune-relevant me-tabolism.[23] These iDegs define a novel monova-lent degrader chemotype and induce ubiquitination of IDO1 by the Cullin2-Ring E3 ligase  KLHDC3, tar-geting IDO1 for proteasomal degradation. Both the small molecule degrader class and the involved E3 ligase are unprecedented.[24] 

Investigation of pseudo-NPs as modulators of miRNA activity unraveled six novel RNA ligand clas-ses which bind to numerous RNA folds and unique motifs of which 259 have not been targeted by a known small molecule binder. Transcriptome-wide mapping of bound RNA-folds showed that ca. 6% of human miRNAs are targetable by six finally triaged hits.[25] Thus, pseudo-NPs may enable targeting of nucleic acids in a wide sense. 

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Selected References 

Selected Reference 1: Laraia L, Garivet G, Foley D J, Kaiser N, Müller S, Zinken S, Pinkert T, Wilke J, Corkery D, Pahl A, Sievers S, Janning P, Arenz C, Wu Y-W, Rodriguez R & Waldmann H* (2020). Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor. Angew Chem Int Ed Engl. 59, 5721-5729, doi: 10.1002/anie.201913712. *Corresponding author 

The molecular mode of action of the new autophagy inhibitor autoquin-1 was identified using image-based morphological profiling in the cell painting assay. A compound-induced fingerprint representing changes in 579 cellular parameters revealed that autoquin accumulates in lysosomes, inhibits their fusion with au-tophagosomes, and sequesters Fe²⁺ in lysosomes, resulting in an increase of lysosomal reactive oxygen species and ultimately cell death. This work demonstrates the potential of the cell painting assay to deconvolute modes of action of small molecules. 

 

Selected Reference 2: Foley D J, Zinken S, Corkery D, Laraia L, Pahl A, Wu Y-W & Waldmann H* (2020). Phenotyping Reveals the Targets of a Pseudo-Natural Product Autophagy Inhibitor. Angew Chem Int Ed Engl. 59, 12470-12476, doi.org/10.1002/anie.202000364. *Corresponding author 

The bioactivity of pseudo-NPs may be best evaluated in target agnostic cell-based assays monitoring entire cellular programs or complex phenotypes. Exploration of indocinchona alkaloid PNP bioactivities in pheno-typic assays identified the novel azaquindole autophagy inhibitors. Characterization of the most potent compound, azaquindole-1, in the morphological cell painting assay, revealed that, in contrast to the parent Cinchona alkaloids, azaquindoles selectively inhibit starvation- and rapamycin-induced autophagy by target-ing the lipid kinase VPS34. 

 

Selected Reference 3: Grigalunas M, Burhop A, Zinken S, Pahl A, Gally J-M, Wild N, Mantel Y, Sievers S, Foley D J, Scheel R, Strohmann C, Antonchick A P & Waldmann H* (2021). Natural Product Fragment Combination to Performance-Diverse Pseudo-Natural Products Nat Commun. 12, 1883; doi.org/10.1038/s41467-021-22174-4. *Corresponding author 

Natural product structure and fragment-based compound development inspire pseudo-natural product design. The synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments provided a 244-member pseudo-natural product collection. The resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrated that bioactivity of pseudo-natural products, guiding natural products, and fragments differ. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. 

 

Selected Reference 4: Akbarzadeh M, Flegel J, Patil S, Shang E, Narayan R, Buchholzer M, Kazemein Jasemi N S, Grigalunas M, Krzyzanowski A, Abegg D, Shuster A, Potowski M, Karatas H, Karageorgis G, Mosaddeghzadeh N, Zischinsky M-L, Merten C, Golz C, Brieger L, Strohmann C, Antonchick A P, Janning P, Adibekian A, Goody R S, Ahmadian M R, Ziegler S & Waldmann H* (2022). The Pseudo-Natural Product Rhonin Targets RHOGDI. Angew Chem Int Ed Engl., 61, e202115193; doi.org/10.1002/anie.202115193. *Corresponding author  

The de novo combination of different 5-membered NP-derived N-heteroatom fragments yielded structurally unprecedented pseudo-NPs in an efficient complexity-generating and enantioselective one-pot synthesis sequence. Investigation of the pseudo-NPs in unbiased phenotypic assays and target identification led to the discovery of the first small-molecule ligand of the RHO GDP-dissociation inhibitor 1 (RHOGDI1), termed Rhonin. Rhonin inhibits the binding of the RHOGDI1 chaperone to GDP-bound RHO GTPases and alters the subcellular localization of RHO GTPases.  

 

Selected Reference 5: Tong Y, Lee Y, Liu X, Childs-Disney JL, Suresh BM, Benhamou RI, Yang C, Li W, Costales MG, Haniff HS, Sievers S, Abegg D, Wegner T, Paulisch TO, Lekah E, Grefe M, Crynen G, Van Meter M, Wang T, Gibaut QMR, Cleveland JL, Adibekian A, Glorius F*, Waldmann H* & Disney MD* (2023). Programming inactive RNA-binding small molecules into bioactive degraders. Nature 618, 169, doi.org/10.1038/s41586-023-06091-8. *Corresponding author

For the discovery of small molecules that bind RNA structures selectively a natural-product inspired small molecule collection and three dimensionally folded RNA structures were investigated, probing >61 million interactions. Six new chemotypes that avidly bind RNA and ~2,000 new RNA folds that bind small molecules were discovered and mined across the human transcriptome to define targetable structures and thus structure-activity relationships for the small molecules and RNA folds transcriptome-wide. For modulation of RNA biology by cleaving the target via a ribonuclease targeting chimera, the substrate specificity for RNase L was overlaid with the binding landscape of the new RNA binders to yield novel degraders, i.e. of microRNA-155 (pre-miR-155) in multiple cell lines and disease settings. These studies illustrate the advantageous properties of natural predict derived RNA ligands that can be converted into potent and specific modulators of RNA function. 

 

Selected Reference 6: Xue G, Xie J, Hinterndorfer M, Cigler M, Dötsch L, Imrichova H, Lampe P, Rezaei Adariani S, Winter GE*, Waldmann H* (2023). Discovery of a Drug-like, Natural Product-Inspired DCAF11 Ligand Chemotype. Nat. Comm. 14, 7908, doi.org/10.1038/s41467-023-43657-6. *Corresponding author 

Bifunctional arylidene-indolinone degraders induced degradation of their targets by the ubiquitin-proteasome system. Target and mechanism identification revealed that they covalently bind DCAF11, a substrate receptor in the CUL4A/B-RBX1-DDB1-DCAF11 E3 ligase. The tempered α, β-unsaturated indolinone electrophiles define a drug-like DCAF11-ligand class that enables exploration of this E3 ligase in chemical biology and medicinal chemistry programs. The arylidene-indolinone scaffold frequently occurs in natural products which raises the question whether E3 ligand classes can be found more widely among natural products and related compounds. 

 

Selected Reference 7: Bag S, Liu J; Patil S, Bonowski J, Koska S, Schölermann B, Zhang R, Wang L, Pahl A, Sievers S, Brieger L, Strohmann C, Ziegler S, Grigalunas M, Waldmann H* (2024). A divergent intermediate strategy yields biologically diverse pseudo-natural products. Nat. Chem. 16, 945, doi.org/10.1038/s41557-024-01458-4. *Corresponding author

The diverse pseudo-natural product (PNP) strategy combines the biological relevance of the PNP concept with synthetic diversification strategies from diversity-oriented synthesis. A diverse PNP collection was synthesized from a common divergent intermediate through developed indole dearomatization methodologies to afford three-dimensional molecular frameworks that could be further diversified via intramolecular coupling and/or carbon monoxide insertion. In total, 154 PNPs were synthesized representing eight different classes. Cheminformatics and biological analyses showed that the PNPs are structurally and biologically diverse between classes. 

 

Selected Reference 8: Xie J, Pahl A, Krzyzanowski A, Krupp A, Liu J, Koska S, Schölermann B, Zhang R, Bonowski J, Sievers S, Strohmann C, Ziegler S, Grigalunas M, Waldmann H* (2023). Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space. Angew. Chem. Int. Ed. Engl., E202310222, doi.org/10.1002/anie.202310222. *Corresponding author 

A pseudo-NP collection was obtained by the unprecedented combination of monoterpene indole alkaloid (MIA) fragments through complexity-generating transformations, resulting in arrangements not currently accessible by biosynthetic pathways. Cheminformatics analyses revealed that both the pseudo-NPs and the MIAs reside in a unique and common area of chemical space with high spatial complexity-density that is only sparsely populated by other natural products and drugs. Investigation of bioactivity guided by morphological profiling identified pseudo-NPs that inhibit DNA synthesis and modulate tubulin. These results demonstrate that the pseudo-NP collection occupies similar biologically relevant chemical space that Nature has endowed MIAs with. 

 

Selected Reference 9: Heinzke AL, Pahl A, Zdrazil B, Leach AR, Waldmann H, Young RJ, Leeson PD* (2024). Occurrence of ‘Natural Selection’ in Successful Small Molecule Drug Discovery. J. Med. Chem. 67, 11226, doi.org/10.1021/acs.jmedchem.4c00811. *Corresponding author 

Published compounds from ChEMBL version 32 were used to seek evidence for the occurrence of “natural selection” in real-world drug discovery. Pseudo-NPs (PNPs), containing NP fragments combined in ways inaccessible by nature, are increasing over time, reaching 67% of clinical compounds first disclosed since 2010. PNPs are 54% more likely to be found in post-2008 clinical versus reference compounds. The majority of target classes show increased clinical compound NP character versus their reference compounds. Only 176 NP fragments appear in >1,000 clinical compounds published since 2008, yet these make up on average 63% of the clinical compound’s core scaffolds. There is untapped potential awaiting exploitation, by applying nature’s building blocks “natural intelligence” to drug design. 

 

Selected Reference 10: Hennes E, Lucas B, Scholes NS, Cheng X-F, Scott DC, Bischoff M, Reich K, Gasper R, Lucas M, Xu TT, Pulvermacher L-M, Dötsch L, Imrichova H, Brause A, Naredla KR, Sievers S, Kumar K, Janning P, Gersch M, Murray PJ, Schulman BA, Winter GE*, Ziegler S, Waldmann H* (2025). Identification of a Mon-ovalent Pseudo-Natural Product Degrader Class Supercharging Degradation of IDO1 by its native E3 KLHDC3. Nature Chemistry 17, in press. bioRxiv: doi.org/10.1101/2024.07.10.602857. *Corresponding author 

 

Pseudo-natural products derived from (-)-myrtanol, termed iDegs inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by boosting IDO1 ubiquitination and degradation by the native IDO1 cullin-RING E3 ligase CRL2KLHDC3. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and, thus, would also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.  

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Future work

Identification of new pseudo-NP “glues”, E3-ligases they recruit, and neo-substrates degraded by them. One of the most relevant findings of our pseudo-NP program is the identification of a new class of mo-lecular glues, i.e. small molecules that recruit ubiq-uitination-inducing E3-ligases to ternary neo-sub-strate complexes and then induce their selective proteasomal degradation. In this booming field, a high demand exists for (i) new degrader classes that may enable selective recruitment of multiple neo substrate proteins, (ii) identification of novel E3-lig-ases that have not been actively employed yet, and (iii) development of novel, broadly applicable assays for identification of target degradation.
The pseudo-NP degrader class identified by us is ac-cessible in a 3-step synthesis and composed of three separately variable parts. We will synthesize a chemically diverse library of several hundred com-pounds and investigate whether they induce degra-dation of different proteins. The molecular glues identified so far (iDegs) recruit the cullin-RING E3 lig-ase CRL2KLHDC3. This ligase has not been employed for small molecule induced target degradation be-fore. We will determine its applicability for induced protein degradation in a wider sense. To reach this goals a novel assay has already been developed to monitor proteome-wide ubiquitination based on mass spectrometric methods.[26]

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General references

1. Grigalunas, M., Brakmann, S., and Waldmann, H. (2022). Chemical Evolution of Natural Product Structure. J Am Chem Soc 144, 3314-3329. 
2. Karageorgis, G., Foley, D.J., Laraia, L., Brakmann, S., and Waldmann, H. (2021). Pseudo Natural Products-Chemical Evolution of Natural Product Structure. Angew Chem Int Ed Engl 60, 15705-15723. 
3. Schneidewind, T., Kapoor, S., Garivet, G., Karageorgis, G., Narayan, R., Vendrell-Navarro, G., Antonchick, A.P., Ziegler, S., and Waldmann, H. (2019). The Pseudo Natural Product Myokinasib Is a Myosin Light Chain Kinase 1 Inhibitor with Unprecedented Chemotype. Cell Chem Biol 26, 512-523 e515. 
4. Ceballos, J., Schwalfenberg, M., Karageorgis, G., Reckzeh, E.S., Sievers, S., Ostermann, C., Pahl, A., Sellstedt, M., Nowacki, J., Carnero Corrales, M.A., et al. (2019). Synthesis of Indomorphan Pseudo-Natural Product Inhibitors of Glucose Transporters GLUT-1 and -3. Angew Chem Int Ed Engl 58, 17016-17025. 
5. Akbarzadeh, M., Flegel, J., Patil, S., Shang, E., Narayan, R., Buchholzer, M., Kazemein Jasemi, N.S., Grigalunas, M., Krzyzanowski, A., Abegg, D., et al. (2022). The Pseudo-Natural Product Rhonin Targets RHOGDI. Angew Chem Int Ed Engl 61, e202115193. 
6. Christoforow, A., Wilke, J., Binici, A., Pahl, A., Ostermann, C., Sievers, S., and Waldmann, H. (2019). Design, Synthesis, and Phenotypic Profiling of Pyrano-Furo-Pyridone Pseudo Natural Products. Angew Chem Int Ed Engl 58, 14715-14723. 
7. Liu, J., Cremosnik, G.S., Otte, F., Pahl, A., Sievers, S., Strohmann, C., and Waldmann, H. (2021). Design, Synthesis, and Biological Evaluation of Chemically and Biologically Diverse Pyrroquinoline Pseudo Natural Products. Angew Chem Int Ed Engl 60, 4648-4656. 
8. Yildirim, O., Grigalunas, M., Brieger, L., Strohmann, C., Antonchick, A.P., and Waldmann, H. (2021). Dynamic Catalytic Highly Enantioselective 1,3-Dipolar Cycloadditions. Angew Chem Int Ed Engl 60, 20012-20020.
9. Burhop, A., Bag, S., Grigalunas, M., Woitalla, S., Bodenbinder, P., Brieger, L., Strohmann, C., Pahl, A., Sievers, S., and Waldmann, H. (2021). Synthesis of Indofulvin Pseudo-Natural Products Yields a New Autophagy Inhibitor Chemotype. Adv Sci (Weinh) 8, e2102042.
10. Patil, S., Cremosnik, G., Dötsch, L., Flegel, J., Schulte, B., Maier, K.C., Zumer, K., Cramer, P., Janning, P., Sievers, S., et al. (2024). The Pseudo-Natural Product Tafbromin Selectively Targets the TAF1 Bromodomain 2. Angew Chem Int Edit 63, e202404645.
11. Liu, J., Flegel, J., Otte, F., Pahl, A., Sievers, S., Strohmann, C., and Waldmann, H. (2021). Combination of Pseudo-Natural Product Design and Formal Natural Product Ring Distortion Yields Stereochemically and Biologically Diverse Pseudo-Sesquiterpenoid Alkaloids. Angew Chem Int Ed Engl 60, 21384-21395.
12. Bag, S., Liu, J., Patil, S., Bonowski, J., Koska, S., Schölermann, B., Zhang, R.R., Wang, L., Pahl, A., Sievers, S., et al. (2024). A divergent intermediate strategy yields biologically diverse pseudo-natural products. Nature Chemistry 16, 299-300.
13. Xie, J., Pahl, A., Krzyzanowski, A., Krupp, A., Liu, J., Koska, S., Scholermann, B., Zhang, R., Bonowski, J., Sievers, S., et al. (2023). Synthetic Matching of Complex Monoterpene Indole Alkaloid Chemical Space. Angew Chem Int Ed Engl 62, e202310222.
14. Gally, J.M., Pahl, A., Czodrowski, P., and Waldmann, H. (2021). Pseudonatural Products Occur Frequently in Biologically Relevant Compounds. J Chem Inf Model 61, 5458-5468.
15. Pahl, A., Grygorenko, O.O., Kondratov, I.S., and Waldmann, H. (2024). Identification of readily available pseudo-natural products. RSC Med Chem 15, 2709-2717.
16. Heinzke, A.L., Pahl, A., Zdrazil, B., Leach, A.R., Waldmann, H., Young, R.J., and Leeson, P.D. (2024). Occurrence of "Natural Selection" in Successful Small Molecule Drug Discovery. J Med Chem 67, 11226-11241.
17. Laraia, L., Garivet, G., Foley, D.J., Kaiser, N., Muller, S., Zinken, S., Pinkert, T., Wilke, J., Corkery, D., Pahl, A., et al. (2020). Image-Based Morphological Profiling Identifies a Lysosomotropic, Iron-Sequestering Autophagy Inhibitor. Angew Chem Int Ed Engl 59, 5721-5729.
18. Foley, D.J., Zinken, S., Corkery, D., Laraia, L., Pahl, A., Wu, Y.W., and Waldmann, H. (2020). Phenotyping Reveals Targets of a Pseudo-Natural-Product Autophagy Inhibitor. Angew Chem Int Ed Engl 59, 12470-12476.
19. Wilke, J., Kawamura, T., Xu, H., Brause, A., Friese, A., Metz, M., Schepmann, D., Wunsch, B., Artacho-Cordon, A., Nieto, F.R., et al. (2021). Discovery of a sigma1 receptor antagonist by combination of unbiased cell painting and thermal proteome profiling. Cell Chem Biol 28, 848-854 e845.
20. Niggemeyer, G., Knyazeva, A., Gasper, R., Corkery, D., Bodenbinder, P., Holstein, J.J., Sievers, S., Wu, Y.W., and Waldmann, H. (2022). Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation. Angew Chem Int Ed Engl 61, e202114328.
21. Knyazeva, A., Li, S., Corkery, D.P., Shankar, K., Herzog, L.K., Zhang, X., Singh, B., Niggemeyer, G., Grill, D., Gilthorpe, J.D., et al. (2024). A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation. Proc Natl Acad Sci U S A 121, e2317680121.
22. Gueret, S.M., Thavam, S., Carbajo, R.J., Potowski, M., Larsson, N., Dahl, G., Dellsen, A., Grossmann, T.N., Plowright, A.T., Valeur, E., et al. (2020). Macrocyclic Modalities Combining Peptide Epitopes and Natural Product Fragments. J Am Chem Soc 142, 4904-4915.
23. Hennes, E., Lampe, P., Dotsch, L., Bruning, N., Pulvermacher, L.M., Sievers, S., Ziegler, S., and Waldmann, H. (2021). Cell-Based Identification of New IDO1 Modulator Chemotypes. Angew Chem Int Ed Engl 60, 9869-9874.MPI Status Report 2025 / Volume II (Scientific Report) 130
24. Hennes, E., Lucas, B., Scholes, N.S., Cheng, X.F., Scott, D.C., Bischoff, M., Reich, K., Gasper, R., Lucas, M., Xu, T.T., et al. (2025). Monovalent Pseudo-Natural Product Degraders Supercharge the Native Degradation of IDO1 by KLHDC3. Nat Chem 17, in press. bioRxiv: doi.org/10.1101/2024.07.10.602857
25. Tong, Y., Lee, Y., Liu, X., Childs-Disney, J.L., Suresh, B.M., Benhamou, R.I., Yang, C., Li, W., Costales, M.G., Haniff, H.S., et al. (2023). Programming inactive RNA-binding small molecules into bioactive degraders. Nature 618, 169-179.
26. Führer, S., Gallant, K., Kaschani, F., Kaiser, M., Janning, P., Waldmann, H., and Gersch, M. (2025). Small molecule induced alterations of protein-polyubiquitination revealed by mass-spectrometric ubiquitome analysis. Angew Chem Int Ed Engl, e202508916.