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.
Biomarkers for patient selection are essential for the successful and rapid development of emerging targeted anti-cancer therapeutics. In this study, we report the discovery of a novel patient selection strategy for the p53–HDM2 inhibitor NVP-CGM097, currently under evaluation in clinical trials. By intersecting high-throughput cell line sensitivity data with genomic data, we have identified a gene expression signature consisting of 13 up-regulated genes that predicts for sensitivity to NVP-CGM097 in both cell lines and in patient-derived tumor xenograft models. Interestingly, these 13 genes are known p53 downstream target genes, suggesting that the identified gene signature reflects the presence of at least a partially activated p53 pathway in NVP-CGM097-sensitive tumors. Together, our findings provide evidence for the use of this newly identified predictive gene signature to refine the selection of patients with wild-type p53 tumors and increase the likelihood of response to treatment with p53–HDM2 inhibitors, such as NVP-CGM097.DOI:
http://dx.doi.org/10.7554/eLife.06498.001
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.
Constrained peptides represent a new class of peptide molecules whose supramolecular structure is controlled via intramolecular covalent bonds, generally to confer upon them biochemical and/or physicochemical properties superior to those of ordinary peptides. Both academia and industry are showing increasing interest in constrained peptides, due to their promise as medicines and tools for drug discovery. The major categories of constrained peptides are macrocyclic peptides 1 and stapled peptides, 2 as illustrated in Figure 1. The related eld of foldamers, which can be thought of as conformationally constrained peptides, has been recently reviewed and will not be discussed here.3 This paper will present an overview of ongoing research and development efforts in this eld, with particular focus on our approach toward constrained peptide research and development.
Why Study Constrained Peptides? PPI Drug TargetsMost investigational and approved drugs to date fall into the broad categories of small molecules or macromolecular biologics, with antibodies, proteins and vaccines representing the predominant forms of approved biologic therapies. Until recently, aside from a small number of natural products, there has been much less progress in designing drugs for the intervening space of medium sized molecules, de ned here as molecules with molecular weights ranging from 500 to 6000 Daltons.From the perspective of small molecule drug discovery, the FDA approval of Bcl 2 inhibitor venetoclax (Figure 2) in 2016, after nearly 30 years of research and development, dem- Abstract: Constrained peptides, namely macrocyclic and stapled peptides, are receiving increasing attention as a promising class of compounds for the inhibition of protein protein interactions (PPI). The current state of peptide therapeutics is discussed, including their merits and challenges, as well as recent technological developments that have enabled a new era in peptide research and development. The technology behind PeptiDream s Peptide Discovery Platform System (PDPS) is described, showing how it can be used to rapidly generate libraries of constrained peptides and obtain detailed SAR information. This technology can provide, with a high rate of success, potent peptide ligands that may be developed as drug candidates themselves, utilized in peptide drug conjugates (PDC), or converted into small molecule drug leads. The outlook for the eld of constrained peptides and their use in the clinic is also described.
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