TY  - JOUR
AB  - Targeting protein-protein interactions (PPIs) is a promising strategy in drug development. However, despite the considerable progress in the field, targeting PPIs with small molecules remains challenging, requiring novel strategies in inhibitor design and subsequent structure-activity relationship (SAR) studies. We have recently identified the PEX5-PEX14 PPI as a novel therapeutic target against diseases related to Trypanosoma infections and discovered small-molecule inhibitors against PEX14 using structure-based drug discovery (SBDD). The current study demonstrates that combining SBDD with quantum mechanical (QM) energy decomposition and deconvolution analysis (EDDA) provides an in-depth understanding of SAR in the newly developed PPI inhibitors class. We obtained diverse dibenzo[b,e]azepin-6(6H)-one PEX14 inhibitors, which resulted from redesigning the central scaffold of one of the previous compound lines and follow-up modifications. The diversification strategy yielded compounds obtained by multicomponent reactions (MCRs), from which the Kabachnik-Fields reaction products were the most potent tricyclic PEX5-PEX14 PPI inhibitors obtained so far. Overall, the activities of the compounds measured with biophysical assays aligned with the QM-derived compound binding energies. Hence, using an advanced computational approach, our results pave an alternative way for SAR rationalization of compounds against PPI targets.
AU  - Nowacki, M.*
AU  - Cardoso Micu Menezes, F.M.
AU  - Pykacz, E.
AU  - Popiołek, M.*
AU  - Napolitano, V.
AU  - Krishna, C.K.*
AU  - Kalel, V.C.*
AU  - Erdmann, R.*
AU  - Fröhlich, T.
AU  - Plettenburg, O.
AU  - Sattler, M.
AU  - Popowicz, G.M.
AU  - Dawidowski, M.*
C1  - 75278
C2  - 57922
CY  - 65 Rue Camille Desmoulins, Cs50083, 92442 Issy-les-moulineaux, France
TI  - Quantum mechanics-driven structure-activity relationship study of PEX5-PEX14 protein-protein interaction inhibitors based on a dibenzo[b,e]azepin-6(6H)-one scaffold.
JO  - Eur. J. Med. Chem.
VL  - 298
PB  - Elsevier France-editions Scientifiques Medicales Elsevier
PY  - 2025
SN  - 0223-5234
ER  - 

TY  - JOUR
AB  - Protein-protein interactions (PPIs) constitute an important but challenging class of molecular targets for small molecules. The PEX5-PEX14 PPI has been shown to play a critical role in glycosome biogenesis and its disruption impairs the metabolism in Trpanosoma parasites, eventually leading to their death. Therefore, this PPI is a potential molecular target for new drugs against diseases caused by Trypanosoma infections. Here, we report a new class of peptidomimetic scaffolds to target the PEX5-PEX14 PPI. The molecular design was based on an oxopiperazine template for the α-helical mimetics. A structural simplification along with modifications of the central oxopiperazine scaffold and addressing the lipophilic interactions led to the development of peptidomimetics that inhibit PEX5-TbPEX14 PPI and display cellular activity against T. b. brucei. This approach provides an alternative approach towards the development of trypanocidal agents and may be generally useful for the design of helical mimetics as PPI inhibitors.
AU  - Marciniak, M.*
AU  - Mroz, P.*
AU  - Napolitano, V.
AU  - Kalel, V.C.*
AU  - Fino, R.
AU  - Pykacz, E.*
AU  - Schliebs, W.*
AU  - Plettenburg, O.
AU  - Erdmann, R.*
AU  - Sattler, M.
AU  - Popowicz, G.M.
AU  - Dawidowski, M.*
C1  - 68443
C2  - 54628
CY  - 65 Rue Camille Desmoulins, Cs50083, 92442 Issy-les-moulineaux, France
TI  - Development of novel PEX5-PEX14 protein-protein interaction (PPI) inhibitors based on an oxopiperazine template.
JO  - Eur. J. Med. Chem.
VL  - 258
PB  - Elsevier France-editions Scientifiques Medicales Elsevier
PY  - 2023
SN  - 0223-5234
ER  - 

TY  - JOUR
AB  - Trypanosomiases are neglected tropical diseases caused by Trypanosoma (sub)species. Available treatments are limited and have considerable adverse effects and questionable efficacy in the chronic stage of the disease, urgently calling for the identification of new targets and drug candidates. Recently, we have shown that impairment of glycosomal protein import by the inhibition of the PEX5-PEX14 protein-protein interaction (PPI) is lethal to Trypanosoma. Here, we report the development of a novel dibenzo[b,f][1,4]oxazepin-11(10H)-one scaffold for small molecule inhibitors of PEX5-PEX14 PPI. The initial hit was identified by a high throughput screening (HTS) of a library of compounds. A bioisosteric replacement approach allowed to replace the metabolically unstable sulphur atom from the initial dibenzo[b,f][1,4]thiazepin-11(10H)-one HTS hit with oxygen. A crystal structure of the hit compound bound to PEX14 surface facilitated the rational design of the compound series accessible by a straightforward chemistry for the initial structure-activity relationship (SAR) analysis. This guided the design of compounds with trypanocidal activity in cell-based assays providing a promising starting point for the development of new drug candidates to tackle trypanosomiases.
AU  - Napolitano, V.*
AU  - Mroz, P.*
AU  - Marciniak, M.*
AU  - Kalel, V.C.*
AU  - Softley, C.
AU  - Janna Olmos, J.D.*
AU  - Tippler, B.G.*
AU  - Schorpp, K.K.
AU  - Rioton, S.
AU  - Fröhlich, T.
AU  - Plettenburg, O.
AU  - Hadian, K.
AU  - Erdmann, R.*
AU  - Sattler, M.
AU  - Popowicz, G.M.
AU  - Dawidowski, M.*
AU  - Dubin, G.*
C1  - 67018
C2  - 53377
TI  - Structure-based design, synthesis and evaluation of a novel family of PEX5-PEX14 interaction inhibitors against Trypanosoma.
JO  - Eur. J. Med. Chem.
VL  - 243
PY  - 2022
SN  - 0223-5234
ER  - 

TY  - JOUR
AB  - The human enzyme 17 beta-hydroxysteroid dehydrogenase 14 (17 beta-HSD14) oxidizes the hydroxyl group at position 17 of estradiol and 5-androstenediol using NAD(+) as cofactor. However, the physiological role of the enzyme remains unclear. We recently described the first class of nonsteroidal inhibitors for this enzyme with compound 1 showing a high 17 beta-HSD14 inhibitory activity. Its crystal structure was used as starting point for a structure-based optimization in this study. The goal was to develop a promising chemical probe to further investigate the enzyme. The newly designed compounds revealed mostly very high inhibition of the enzyme and for seven of them the crystal structures of the corresponding inhibitor enzyme complexes were resolved. The crystal structures disclosed that a small change in the substitution pattern of the compounds resulted in an alternative binding mode for one inhibitor. The profiling of a set of the most potent inhibitors identified 13 (K-i = 9 nM) with a good selectivity profile toward three 17 beta-HSDs and the estrogen receptor alpha. This inhibitor displayed no cytotoxicity, good solubility, and auspicious predicted bioavailability. Overall, 13 is a highly interesting 17 beta-HSD14 inhibitor, which might be used as chemical probe for further investigation of the target enzyme.
AU  - Braun, F.*
AU  - Bertoletti, N.*
AU  - Möller, G.
AU  - Adamski, J.
AU  - Frotscher, M.*
AU  - Guragossian, N.*
AU  - Madeira Gírio, P.A.*
AU  - Le Borgne, M.*
AU  - Ettouati, L.*
AU  - Falson, P.*
AU  - Müller, S.*
AU  - Vollmer, G.*
AU  - Heine, A.*
AU  - Klebe, G.*
AU  - Marchais-Oberwinkler, S.*
C1  - 53595
C2  - 44674
CY  - 65 Rue Camille Desmoulins, Cs50083, 92442 Issy-les-moulineaux, France
SP  - 61-76
TI  - Structure-based design and profiling of novel 17 beta-HSD14 inhibitors.
JO  - Eur. J. Med. Chem.
VL  - 155
PB  - Elsevier France-editions Scientifiques Medicales Elsevier
PY  - 2018
SN  - 0223-5234
ER  - 

TY  - JOUR
AB  - USP2a is a deubiquitinating protease that rescues its target proteins from destruction by the proteasome by reversing the process of protein ubiquitination. USP2a shows oncogenic properties in vivo and has been found to be a specific activator of cyclin D1. Many types of cancers are addicted to cyclin D1 expression. Targeting USP2a is a promising strategy for cancer therapy but little progress has been made in the field of inhibition of USP2a. Using NMR-based fragment screening and biophysical binding assays, we have discovered small molecules that bind to USP2a. Iterations of fragment combination and structure-driven design identified two 5-(2-thienyl)-3-isoxazoles as the inhibitors of the USP2a-ubiquitin protein-protein interaction. The affinity of these molecules for the catalytic domain of USP2a parallels their ability to interfere with USP2a binding to ubiquitin in vitro. Altogether, our results establish the 5-(2-thienyl)-3-isoxazole pharmacophore as an attractive starting point for lead optimization.
AU  - Tomala, M.D.*
AU  - Magiera-Mularz, K.*
AU  - Kubica, K.*
AU  - Krzanik, S.*
AU  - Zieba, B.*
AU  - Musielak, B.*
AU  - Pustula, M.*
AU  - Popowicz, G.M.
AU  - Sattler, M.
AU  - Dubin, G.*
AU  - Skalniak, L.*
AU  - Holak, T.A.*
C1  - 53237
C2  - 44646
SP  - 261-267
TI  - Identification of small-molecule inhibitors of USP2a.
JO  - Eur. J. Med. Chem.
VL  - 150
PY  - 2018
SN  - 0223-5234
ER  -