Phenotypic Discovery of Triazolo[1,5-<i>c</i>]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype

Wesseler, Fabian; Lohmann, Stefan; Riege, Daniel; Halver, Jonas; Roth, Aileen; Pichlo, C.; Weber, Sabrina; Takamiya, Masanari; Müller, Eva; Ketzel, Jana; Flegel, Jana; Gihring, Adrian; Rastegar, Sepand; Bertrand, Jessica; Baumann, Ulrich; Knippschild, Uwe; Peifer, Christian; Sievers, Sonja; Waldmann, Herbert; Schade, Dennis

doi:10.1021/acs.jmedchem.2c01199

Cited by 7 publications

(10 citation statements)

References 59 publications

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“… , Inhibiting this checkpoint might cause genomic instability in rapidly replicating cells like pluripotent stem cells at the onset of differentiation . In fact, we have observed pronounced cell toxicity already at low doses of PD407824 in all our BMP-dependent assay setups that limited its use as a reference compound. , …”

Section: Bmp Stimulatorsmentioning

confidence: 84%

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Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Riege,

Herschel,

Fenkl

et al. 2023

ACS Pharmacol. Transl. Sci.

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The bone morphogenetic protein (BMP) pathway is highly conserved and plays central roles in health and disease. The quality and quantity of its signaling outputs are regulated at multiple levels, offering pharmacological options for targeted modulation. Both target-centric and phenotypic drug discovery (PDD) approaches were applied to identify small-molecule BMP inhibitors and stimulators. In this Review, we accumulated and systematically classified the different reported chemotypes based on their targets as well as modes-of-action, and herein we illustrate the discovery history of selected candidates. A comprehensive summary of available biochemical, cellular, and in vivo activities is provided for the most relevant BMP modulators, along with recommendations on their preferred use as chemical probes to study BMP-related (patho)physiological processes. There are a number of high-quality probes used as BMP inhibitors that potently and selectively interrogate the kinase activities of distinct type I (16 chemotypes available) and type II receptors (3 chemotypes available). In contrast, only a few high-quality BMP stimulator modalities have been introduced to the field due to a lack of profound target knowledge. FK506-derived macrolides such as calcineurin-sparing FKBP12 inhibitors currently represent the best-characterized chemical tools for direct activation of BMP-SMAD signaling at the receptor level. However, several PDD campaigns succeeded in expanding the druggable space of BMP stimulators. Albeit the majority of them do not entirely fulfill the strict chemical probe criteria, many chemotypes exhibit unique and unrecognized mechanisms as pathway potentiators or synergizers, serving as valuable pharmacological tools for BMP perturbation.

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Section: Bmp Stimulatorsmentioning

confidence: 84%

“…In view of such intrinsic pathway selectivity concerns, the recent discovery of triazolo[1,5- c ]quinazoline CGS-15943 (Figure B) as a new-in-class BMP amplifier (here classified as “potentiator”) presents a significant leap forward . It was discovered from the same stem-cell-based PDD platform as Chromenone 1 .…”

Section: Bmp Stimulatorsmentioning

confidence: 99%

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Riege,

Herschel,

Fenkl

et al. 2023

ACS Pharmacol. Transl. Sci.

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“…Employing our recently disclosed phenotypic screening platform, , we identified a cluster of 3-aryl- and 4-indoyl-substituted maleimides from an in-house compound library, which were initially reported as angiogenesis inhibitors . Here, the compounds struck our interest for their osteogenic induction potential (Alp activity, C2C12 cells).…”

Section: Resultsmentioning

confidence: 99%

“…2 With the identification of Chromenone 1 and CGS-15943 by successful screening and deconvolution, we already yielded two potent modulators of BMP signaling with distinct mechanisms and molecular targets (Figure 1). 2,3 Herein, the discovery of an interconnection between PI3K/CK1 pathways and BMP-SMAD dynamics underlined the power of PDD to not only identify new small-molecule agents but to unravel unprecedented processes of the underlying pathway biology.…”

mentioning

confidence: 99%

Identification of Maleimide-Fused Carbazoles as Novel Noncanonical Bone Morphogenetic Protein Synergizers

Riege,

Herschel,

Heintze

et al. 2023

ACS Pharmacol. Transl. Sci.

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Morphogenic signaling pathways govern embryonic development and tissue homeostasis on the cellular level. Precise control of such signaling events paves the way for innovative therapeutic approaches in the field of regenerative medicine. In line with these notions, bone morphogenic protein (BMP) is a major osteogenic driver and pharmacological stimulation of BMP signaling holds supreme potential for diseases and defects of the skeleton. Efforts to identify small-molecule modalities that activate or potentiate the BMP pathway have primarily been focused on the canonical signaling cascade. Here, we describe the phenotypic identification and development of specific carbazolomaleimides 2 as novel noncanonical BMP synergizers with submicromolar osteogenic cellular potency. The devised chemical tools are characterized to specifically regulate Id gene expression in a SMAD-independent, yet highly BMP-dependent fashion. Mechanistic studies revealed that GSK3 inhibition and increased β-catenin levels are partly responsible for this activity. The utility of the new BMP synergizer profile was further exemplified by showing how the synergistic action of canonical and noncanonical BMP enhancers additively amplifies BMP-dependent osteogenic outputs. Carbazolomaleimide 2b serves as a new and unique pharmacological tool for the modulation and study of the BMP pathway.

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“…Accordingly, compared to the more largely explored and synthetically accessible 1,2,4-triazoloquinoxalines ( Alswah et al, 2018 ; El-Attar et al, 2018 ; Houa et al, 2020 ; Wesseler et al, 2022 ), only few applications on the 1,2,3-triazoloquinoxaline counterpart have been reported in literature, most probably due to the available somewhat outdated synthetic protocols that lack versatility for quick scaffold decoration and derivatization.…”

Section: Introductionmentioning

confidence: 99%

Rejuvenating the [1, 2, 3]-triazolo [1,5-a]quinoxalin-4(5H)-one scaffold: Synthesis and derivatization in a sustainable guise and preliminary antimicrobial evaluation

Pelliccia

Alfano²,

Assunção³

et al. 2023

Front. Chem.

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The [1,2,3]-triazolo [1,5-a] quinoxalin-4(5H)-one scaffold and its analogues triazole-fused heterocyclic compounds are relevant structural templates in both natural and synthetic biologically active compounds. However, their medicinal chemistry applications are often limited due to the lack of synthetic protocols combining straightforward generation of the central core while also allowing extensive decoration activity for drug discovery purposes. Herein, we report a “refreshed” synthesis of the [1,2,3]-triazolo [1,5-a]quinoxalin-4(5H)-one core, encompassing the use of eco-compatible catalysts and reaction conditions. We have also performed a sustainable and extensive derivatization campaign at both the endocyclic amide nitrogen and the ester functionality, comprehensively exploring the reaction scope and overcoming some of the previously reported difficulties in introducing functional groups on this structural template. Finally, we unveiled a preliminary biological investigation for the newly generated chemical entities. Our assessment of the compounds on different bacterial species (two S. aureus strains, three P. aeruginosa strains, K. pneumonia), and two fungal C. albicans strains, as well as the evaluation of their activity on S. epidermidis biofilm formation, foster further optimization for the retrieved hit compounds 9, 14, and 20.

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Phenotypic Discovery of Triazolo[1,5-c]quinazolines as a First-In-Class Bone Morphogenetic Protein Amplifier Chemotype

Cited by 7 publications

References 59 publications

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Small-Molecule Probes as Pharmacological Tools for the Bone Morphogenetic Protein Signaling Pathway

Identification of Maleimide-Fused Carbazoles as Novel Noncanonical Bone Morphogenetic Protein Synergizers

Rejuvenating the [1, 2, 3]-triazolo [1,5-a]quinoxalin-4(5H)-one scaffold: Synthesis and derivatization in a sustainable guise and preliminary antimicrobial evaluation

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