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The p53–MDM2 interaction is an anticancer drug target under investigation in the clinic. Our compound NVP-CGM097 is one of the small molecule inhibitors of this protein–protein interaction currently evaluated in cancer patients. As part of our effort to identify new classes of p53–MDM2 inhibitors that could lead to additional clinical candidates, we report here the design of highly potent inhibitors having a pyrazolopyrrolidinone core structure. The conception of these new inhibitors originated in a consideration on the MDM2 bound conformation of the dihydroisoquinolinone class of inhibitors to which NVP-CGM097 belongs. This work forms the foundation of the discovery of HDM201, a second generation p53–MDM2 inhibitor that recently entered phase I clinical trial. [ABSTRACT FROM AUTHOR]

Focuses on the development of a synthetic method for functionalized cyclopentanones on the basis of a [3+2] cycloaddition reaction. Discussion on the features of regioselectivity; Analysis of the reactions of 1b withvinyl sulfides exhibited surprisingly high steroselectivity; Results of the study.

Presents the highly enantioselective synthesis of anthracycline precursors from a chirality-transfer ene reaction. Products obtained from the selective preparation of intermediates; Schematic representation of the reaction pathway.

Graphical abstract Highlights • Novel rationally designed p53-MDM2 inhibitor scaffold. • Structural proof of concept by x-ray crystallography. • Optimization of metabolic stability. • In vivo proof of concept with high efficacy. Abstract Small molecule inhibitors of the p53-MDM2 protein complex are under intense investigation in clinical trials as anti-cancer agents, including our first generation inhibitor NVP-CGM097. We recently described the rational design of a novel pyrazolopyrrolidinone core as a new lead structure and now we report on the synthesis and optimization of this to provide a highly potent lead compound. This new compound displayed excellent oral efficacy in our preclinical mechanistic in vivo model and marked a significant milestone towards the identification of our second generation clinical candidate NVP-HDM201. [ABSTRACT FROM AUTHOR]

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein–protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11 , a low nanomolar inhibitor of the p53–MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53–MDM2 inhibitors. [ABSTRACT FROM AUTHOR]

Abstract: Capitalizing on crystal structure information obtained from a previous effort in the search for non peptide inhibitors of the p53–MDM2 interaction, we have discovered another new class of compounds able to disrupt this protein–protein interaction, an important target in oncology drug research. The new inhibitors, based on a tetra-substituted imidazole scaffold, have been optimized to low nanomolar potency in a biochemical assay following a structure-guided approach. An appropriate strategy has allowed us to translate the high biochemical potency in significant anti-proliferative activity on a p53-dependent MDM2 amplified cell line. [Copyright &y& Elsevier]

Abstract: Disrupting the interaction between the p53 tumor suppressor and its regulator MDM2 is a promising therapeutic strategy in anticancer drug research. In our search for non peptide inhibitors of this protein–protein interaction, we have devised a ligand design concept exploiting the central position of Val 93 in the p53 binding pocket of MDM2. The design of molecules based on this concept has allowed us to rapidly identify compounds having a 3-imidazolyl indole core structure as the first representatives of a new class of potent inhibitors of the p53–MDM2 interaction. [Copyright &y& Elsevier]

Abstract: A novel series of pyrazolo[1,5a]pyrimidines was optimized to target lymphocyte-specific kinase (Lck). An efficient synthetic route was developed and SAR studies toward activity and selectivity are described, leading to Lck inhibitors with enzymatic, cellular and in vivo potency. [Copyright &y& Elsevier]

p53 tumor suppressor activity is negatively regulated through binding to the oncogenic proteins Hdm2 and HdmX. The p53 residues Leu26, Trp23, and Phe19 are crucial to mediate these interactions. Inhibiting p53 binding to both Hdm2 and HdmX should be a promising clinical approach to reactivate p53 in the cancer setting, but previous studies have suggested that the discovery of dual Hdm2/HdmX inhibitors will be difficult. We have determined the crystal structures at 1.3 A of the N-terminal domain of HdmX bound to two p53 peptidomimetics without and with a 6-chlorine substituent on the indole (which binds in the same subpocket as Trp23 of p53). The latter compound is the most potent peptide-based antagonist of the p53-Hdm2 interaction yet to be described. The x-ray structures revealed surprising conformational changes of the binding cleft of HdinX, including an "open conformation" of Tyr99 and unexpected "cross-talk" between the Tip and Leu pockets. Notably, the 6-chloro p53 peptidomimetic bound with high affinity to both HdmX and Hdm2 (Kd values of 36 and 7 nM, respectively). Our results suggest that the development of potent dual inhibitors for HdmX and Hdm2 should be feasible. They also reveal possible conformational states of HdmX, which should lead to a better prediction of its interactions with potential biological partners. [ABSTRACT FROM AUTHOR]

Abstract: We describe here orally active and brain-penetrant cathepsin S selective inhibitors, which are virtually devoid of hERG K+ channel affinity, yet exhibit nanomolar potency against cathepsin S and over 100-fold selectivity to cathepsin L. The new non-peptidic inhibitors are based on a 2-cyanopyrimidine scaffold bearing a spiro[3.5]non-6-yl-methyl amine at the 4-position. The brain-penetrating cathepsin S inhibitors demonstrate potential clinical utility for the treatment of multiple sclerosis and neuropathic pain. [Copyright &y& Elsevier]

Abstract: We describe here a novel 4-amino-2-cyanopyrimidine scaffold for nonpeptidomimetic cathepsin S selective inhibitors. Some of the synthesized compounds have sub-nanomolar potency and high selectivity toward cathepsin S along with promising pharmacokinetic and physicochemical properties. The key structural features of the inhibitors consist of a combination of a spiro[2.5]oct-6-ylmethylamine P2 group at the 4-position, a small or polar P3 group at the 5-position and/or a polar group at the 6-position of the pyrimidine. [Copyright &y& Elsevier]

Abstract: Nonpeptidic, selective, and potent cathepsin S inhibitors were derived from an in-house pyrrolopyrimidine cathepsin K inhibitor by modification of the P2 and P3 moieties. The pyrrolopyrimidine-based inhibitors show nanomolar inhibition of cathepsin S with over 100-fold selectivity against other cysteine proteases, including cathepsin K and L. Some of the inhibitors showed cellular activities in mouse splenocytes as well as oral bioavailabilities in rats. [Copyright &y& Elsevier]

Abstract: Pyrrolopyrimidine, a novel scaffold, allows to adjust interactions within the S3 subsite of cathepsin K. The core intermediate 10 facilitated the P3 optimization and identified highly potent and selective cathepsin K inhibitors 11–20. [Copyright &y& Elsevier]