Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53–MDM2 interaction with a distinct binding mode

Gessier, François; Kallen, Joerg; Jacoby, Edgar; Chêne, Patrick; Stachyra, Therese‐Marie; Ruetz, Stephan; Jeay, Sébastien; Holzer, Philipp; Masuya, Keiichi; Furet, Pascal

doi:10.1016/j.bmcl.2015.06.058

Cited by 56 publications

(46 citation statements)

References 25 publications

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“…14 An initial optimization effort guided by crystal structure information afforded compound 2, a potent MDM2 inhibitor with an IC 50 of 8 nM in the TR-FRET biochemical assay (Figure 1 and Table 1). 19 Compound 2 demonstrated significant activity in the SJSA-1 cell proliferation assay (IC 50 of 3.86 µM) and was therefore an interesting starting point for further development.…”

Section: Development Of the Dihydroisoquinolinone Series Using X-ray mentioning

confidence: 99%

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

et al. 2015

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As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species.

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Section: Development Of the Dihydroisoquinolinone Series Using X-ray mentioning

confidence: 99%

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

et al. 2015

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“…[20][21][22] Several studies have used interface residues of the protein ligand of a protein-protein interaction to guide the design of small-molecule inhibitors in virtuals creening and lead optimization. [23][24][25][26][27][28][29] The most common approach is based on pharmacophore modeling to enrich libraries for compounds that possessed substituents that not only adopted the same position as the amino acid side chain, but also possessed similarphysicochemical properties to the side chain.T his strategy has workedr easonably well, although it is worth mentioning that there are no examples to date of small molecules that disrupt tight protein-protein interactions that emerged directly from virtual screening. Another strategy consists of finding molecules that bind directly to the receptor with the hope that these compounds will disrupt the protein-protein interaction.…”

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confidence: 99%

Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small‐Molecule Antagonists

Bum‐Erdene

et al. 2017

ChemMedChem

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Tight protein-protein interactions (Kd < 100 nM) that occur over a large binding interface (> 1,000 Å2) are highly challenging to disrupt with small molecules. Historically, the design of small molecules to inhibit protein-protein interactions has focused on mimicking the position of interface protein ligand side chains. Here, we explore mimicry of the pairwise intermolecular interactions of the native protein ligand with residues of the protein receptor to enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions. We use the high-affinity interaction (Kd = 1 nM) between the urokinase receptor (uPAR) and its ligand urokinase (uPA) to test our methods. We introduce three methods for rank-ordering small molecules docked to uPAR: (i) a new fingerprint approach that represents uPA’s pairwise interaction energies with uPAR residues; (ii) a pharmacophore approach to identify small molecules that mimic the position of uPA interface residues; and (iii) a combined fingerprint and pharmacophore approach. Our work led to small molecules with novel chemotypes that inhibited a tight uPAR•uPA protein-protein interaction with single-digit micromolar IC50s. We also report the extensive work that identified several of the hits as either lacking stability, thiol reactive, or redox active. This work suggests that mimicking the binding profile of the native ligand and the position of interface residues can be an effective strategy to enrich commercial libraries for small-molecule inhibitors of tight protein-protein interactions.

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“…[19] These efforts culminated in the discovery of NVP-HDM201 (compound 8,F igure 1a nd Figure3C), ad ihydropyrroloimidazole analogue. Structures of Novartis Hdm2 inhibitors for which previouslyunpublished details of the X-ray structure determinations are reported herein:i midazolyl-substituted indole compound 1, [14] tetrasubstitutedimidazole compound 2, [15] dihydroisoquinolinone compound 3, [17] dihydroisoquinolinone compound 4, [18] clinical trial compound NVP-CGM097(5), [18] Herein we reportf our new X-ray structures for Hdm2 complexes and five new X-ray structures for HdmX complexes (compounds shown in Figure 2). [20] In the last few years, severalo ther companies have progresseds mall-molecule Hdm2 inhibitors into clinicalt rials, and reviewshave recently been published.…”

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“…[16] From this effort, ad ihydroisoquinolinone compound wasi dentified as an interesting hitt hat inhibited the p53-Hdm2i nteraction with an IC 50 value of 0.54 mm in the TR-FRETassay.A fter someo ptimization trials, the first X-ray structure (for compound 3,F igure 1) then surprisingly revealed an unprecedented binding mode (rotation by~1808 with respect to binding mode hypothesis). [17] Subsequent medicinal chemistry exploration and extensive X-ray-supported optimization (e.g.,w ith X-ray crystal structuref or compound 4, Figure 1) then culminated in the discovery of NVP-CGM097 (compound 5,F igure 1a nd Figure3B), the first Novartis p53-Hdm2 inhibitor compound to successfully progress through toxicology studies and into phase 1c linical trials. [18] Subsequently,b ased on the X-ray structure information for previous chemicals eries, we designedf used 5-5 bicyclic systems( which shouldr eplace the non-flatd ihydroisoquinolinone core and thus adopt ab inding mode again consistent with the "central valine concept") bearings ubstituents conforming to the Leu26 and Trp23 sub-pocket pharmacophores (meta-chlorophenyl ring for the former and a para-chlorophenyl ring for the latter).…”

mentioning

confidence: 99%

“…[8,21] Figure 1. Structures of Novartis Hdm2 inhibitors for which previouslyunpublished details of the X-ray structure determinations are reported herein:i midazolyl-substituted indole compound 1, [14] tetrasubstitutedimidazole compound 2, [15] dihydroisoquinolinone compound 3, [17] dihydroisoquinolinone compound 4, [18] clinical trial compound NVP-CGM097(5), [18] dihydropyrrolopyrazole compound 6, [19] dihydropyrroloimidazole compound 7, [19] and clinical trial compoundNVP-HDM201 (8). [20] Herein we reportf our new X-ray structures for Hdm2 complexes and five new X-ray structures for HdmX complexes (compounds shown in Figure 2).…”

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Structural States of Hdm2 and HdmX: X‐ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes

et al. 2019

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Hdm2 (human MDM2, human double minute 2 homologue) counteracts p53 function by direct binding to p53 and by ubiquitin‐dependent p53 protein degradation. Activation of p53 by inhibitors of the p53–Hdm2 interaction is being pursued as a therapeutic strategy in p53 wild‐type cancers. In addition, HdmX (human MDMX, human MDM4) was also identified as an important therapeutic target to efficiently reactivate p53, and it is likely that dual inhibition of Hdm2 and HdmX is beneficial. Herein we report four new X‐ray structures for Hdm2 and five new X‐ray structures for HdmX complexes, involving different classes of synthetic compounds (including the worldwide highest resolutions for Hdm2 and HdmX, at 1.13 and 1.20 Å, respectively). We also reveal the key additive 18‐crown‐ether, which we discovered to enable HdmX crystallization and show its stabilization of various Lys residues. In addition, we report the previously unpublished details of X‐ray structure determinations for eight further Hdm2 complexes, including the clinical trial compounds NVP‐CGM097 and NVP‐HDM201. An analysis of all compound binding modes reveals new and deepened insight into the possible adaptations and structural states of Hdm2 (e.g., flip of F55, flip of Y67, reorientation of H96) and HdmX (e.g., flip of H55, dimer induction), enabling key binding interactions for different compound classes. To facilitate comparisons, we used the same numbering for Hdm2 (as in Q00987) and HdmX (as in O15151, but minus 1). Taken together, these structural insights should prove useful for the design and optimization of further selective and/or dual Hdm2/HdmX inhibitors.

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Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53–MDM2 interaction with a distinct binding mode

Cited by 56 publications

References 25 publications

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors

Mimicking Intermolecular Interactions of Tight Protein–Protein Complexes for Small‐Molecule Antagonists

Structural States of Hdm2 and HdmX: X‐ray Elucidation of Adaptations and Binding Interactions for Different Chemical Compound Classes

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