Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains

Hoffer, Laurent; Roché, Philippe; Morelli, Xavier

doi:10.1007/978-1-0716-1166-1_16

Cited by 3 publications

(6 citation statements)

References 55 publications

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“…These low affinities observed for these hits from the primary screening were expected because PDZ domains belong to protein–protein interaction interfaces, and are considered poorly druggable targets compared to enzymes. However, several small organic compounds have been reported in the literature as inhibitors of PDZ domains (Figure S2) but they mainly exhibited inhibition in the 10 micromolar range, even after intensive SAR and optimization studies . Of particular note, all molecules that were expected to target the larger induced-fit subpocket (from PDB code 1W9E) showed no activity.…”

Section: Resultsmentioning

confidence: 99%

“…However, several small organic compounds have been reported in the literature as inhibitors of PDZ domains 7 (Figure S2) but they mainly exhibited inhibition in the 10 micromolar range, even after intensive SAR and optimization studies. 7 Of particular note, all molecules that were expected to target the larger induced-fit subpocket (from PDB code 1W9E) showed no activity. One hypothesis was that the energy cost associated with the opening of the pocket was too high for these chemicals.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Finally, this whole strategy can be easily applied to any protein with a known 3D structure. Methyl (2S)- 3-methyl-2-[(2S)-3-methyl-2-(1-oxo-3H-isoindol-2yl)butanamido]pentanoate (7). 1 H NMR (CDCl 3 , 250 MHz): δ = 7.83 1H),1H),2H),6.67 (bd,J = 8.2 Hz,1H),4.54 (d,J = 17.5 Hz,1H),4.42 (dd,J = 8.4 and 5.0 Hz,1H),4.35 (d,J = 17.4 Hz,1H),4.33 (d,J = 11.2 Hz,1H),3.65 (s,3H),1H),1H), 1.28−1.02 (m, 2H), 0.97 (d, J = 6.5 Hz, 3H), 0.81 (d, J = 6.6 Hz, 3H), 0.74 (d, J = 7.4 Hz, 3H), 0.70 (d, J = 7.0 Hz, 3H).…”

Section: ■ Conclusionmentioning

confidence: 99%

“…Protein−protein interactions (PPIs), more particularly those of PDZ domains, which are protein modules that participate in many signaling pathways, represent an attractive but particularly challenging target for drug discovery. 7 PDZ domains recognize the C-termini of their protein partners and are critical for regulating several biological events such as scaffolding, trafficking and signaling cascades. More precisely, the last C-terminal residue of the PDZ partner is hydrophobic and its side chain is located within a hydrophobic pocket, while the terminal carboxylic group is involved in a canonical hydrogen-bond network.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Protein–protein interactions (PPIs), more particularly those of PDZ domains, which are protein modules that participate in many signaling pathways, represent an attractive but particularly challenging target for drug discovery . PDZ domains recognize the C-termini of their protein partners and are critical for regulating several biological events such as scaffolding, trafficking and signaling cascades.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach

et al. 2023

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The rapid identification of early hits by fragmentbased approaches and subsequent hit-to-lead optimization represents a challenge for drug discovery. To address this challenge, we created a strategy called "DOTS" that combines molecular dynamic simulations, computer-based library design (chemoDOTS) with encoded medicinal chemistry reactions, constrained docking, and automated compound evaluation. To validate its utility, we applied our DOTS strategy to the challenging target syntenin, a PDZ domain containing protein and oncology target. Herein, we describe the creation of a "best-in-class" sub-micromolar small molecule inhibitor for the second PDZ domain of syntenin validated in cancer cell assays. Key to the success of our DOTS approach was the integration of protein conformational sampling during hit identification stage and the synthetic feasibility ranking of the designed compounds throughout the optimization process. This approach can be broadly applied to other protein targets with known 3D structures to rapidly identify and optimize compounds as chemical probes and therapeutic candidates.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Conclusionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach

et al. 2023

Self Cite

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Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library

Park,

Fan,

Chamakuri

et al. 2023

J. Med. Chem.

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β-Lactamase enzymes hydrolyze and thereby provide bacterial resistance to the important β-lactam class of antibiotics. The OXA-48 and NDM-1 β-lactamases cause resistance to the last-resort β-lactams, carbapenems, leading to a serious public health threat. Here, we utilized DNA-encoded chemical library (DECL) technology to discover novel β-lactamase inhibitors. We exploited the βlactamase enzyme−substrate binding interactions and created a DECL targeting the carboxylate-binding pocket present in all β-lactamases. A library of 10 6 compounds, each containing a carboxylic acid or a tetrazole as an enzyme recognition element, was designed, constructed, and used to identify OXA-48 and NDM-1 inhibitors with micromolar to nanomolar potency. Further optimization led to NDM-1 inhibitors with increased potencies and biological activities. This work demonstrates that the carboxylate-binding pocket-targeting DECL, designed based on substrate binding information, aids in inhibitor identification and led to the discovery of novel non-β-lactam pharmacophores for the development of β-lactamase inhibitors for enzymes of different structural and mechanistic classes.

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Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis

Pradhan,

Modi,

Maji

et al. 2023

Molecular Cancer Therapeutics

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Genome-wide gene expression analysis and animal modeling indicate that melanoma differentiation associated gene-9 (mda-9, Syntenin, Syndecan binding protein, referred to as MDA-9/Syntenin) positively regulates melanoma metastasis. The MDA-9/Syntenin protein contains two tandem PDZ domains serving as a nexus for interactions with multiple proteins that initiate transcription of metastasis-associated genes. Although targeting either PDZ domain abrogates signaling and prometastatic phenotypes, the integrity of both domains is critical for full biological function. Fragment-based drug discovery and NMR identified PDZ1i, an inhibitor of the PDZ1 domain that effectively blocks cancer invasion in vitro and in vivo in multiple experimental animal models. To maximize disruption of MDA-9/Syntenin signaling, an inhibitor has now been developed that simultaneously binds and blocks activity of both PDZ domains. PDZ1i was joined to the second PDZ binding peptide (TNYYFV) with a PEG linker, resulting in PDZ1i/2i (IVMT-Rx-3) that engages both PDZ domains of MDA-9/Syntenin. IVMT-Rx-3 blocks MDA-9/Syntenin interaction with Src, reduces NF-κB activation, and inhibits MMP-2/MMP-9 expression, culminating in repression of melanoma metastasis. The in vivo antimetastatic properties of IVMT-Rx-3 are enhanced when combined with an immune-checkpoint inhibitor. Collectively, our results support the feasibility of engineering MDA-9 dual-PDZ inhibitors with enhanced antimetastatic activities and applications of IVMT-Rx-3 for developing novel therapeutic strategies effectively targeting melanoma and in principle, a broad spectrum of human cancers that also overexpress MDA-9/Syntenin.

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Rational Design of PDZ Domain Inhibitors: Discovery of Small Organic Compounds Targeting PDZ Domains

Cited by 3 publications

References 55 publications

Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach

Discovery of a PDZ Domain Inhibitor Targeting the Syndecan/Syntenin Protein–Protein Interaction: A Semi-Automated “Hit Identification-to-Optimization” Approach

Exploiting the Carboxylate-Binding Pocket of β-Lactamase Enzymes Using a Focused DNA-Encoded Chemical Library

Dual Targeting of the PDZ1 and PDZ2 Domains of MDA-9/Syntenin Inhibits Melanoma Metastasis

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