The p53-MDM2/MDMX axis - A chemotype perspective

The protein-protein interaction (PPI) of the tumor suppressor p53 and its negative regulator MDM2 consists of the most intense studied PPI with a group of small molecular weight antagonists described and many more disclosed in patent literature. Due to the Å-level structural insight into p53 interaction with MDM2 there is a reasonable understanding of the requirements of the molecules to bind. In contrast and despite the very close homology and 3-D similarity no potent MDMX antagonist has been disclosed up to date. The current review summarizes the different disclosed chemotypes for MDM2 including a discussion of the cocrystal structures. Structures and approaches to reconstitute functional p53 from mutated p53 are presented. Finally new screening methods and recent biotech deals based on p53 are discussed

Rapid Combinatorial Access to Macrocyclic Ansa-peptoids and Peptides with a Natural Product Like Core Structure

14-Membered ansa-cyclopeptide alkaloids are among the most abundant natural macrocycles and thus valuable templates for diversity-oriented synthesis with biological relevance. A rapid synthesis of the core structure is conceivable by a combination of an Ugi four-component reaction with bifunctional building blocks to form the dipeptoid part, followed by a suitable macrocyclization reaction. The latter step is crucial, and an uncommon macroetherification gave the best results. The use of ammonium salts allows direct access to peptides instead of peptoids. Depending on the substitution pattern, some cyclopeptoids show planar chirality despite free rotation of the phenylene group. © Georg Thieme Verlag Stuttgart

Structure-activity and high-content imaging analyses of novel tubulysins

The synthesis and biological evaluation of three tubulysin analogs provides the first structure-activity relationship in this family of potent cytotoxic myxobacteria metabolites. Most importantly, the labile N,O-acetal at N 14 is not essential for biological activity. Further, structural simplifications are possible without abolishing biological activities. The N-terminal amino acid can be replaced with N-methylsarcosine, and the configuration at the acetoxy-bearing stereocenter at C11 is important but not critical for almost all aspects of the biological profile. Our data encourage further development of these compounds as potential therapeutic agents in cancer treatment. © 2007 The Authors

Mdm2 and MdmX inhibitors for the treatment of cancer:a patent review (2011-present)

Introduction: One of the hallmarks of cancer cells is the inactivation of the p53 pathway either due to mutations in the p53 gene or over-expression of negative regulators, Mdm2 and/or MdmX. Pharmacological disruption of the Mdm2/X-p53 interaction to restore p53 activity is an attractive concept, aiming at a targeted and non-toxic cancer treatment. Areas covered: The introduction covers the biological role of p53 pathway and its regulation by Mdm2 and MdmX in normal and cancer cells and the current repertoire and development status of inhibitors of the Mdm2/X-p53 interaction for the treatment of cancer. The main part of the article covers patents and patent applications describing small molecule inhibitors of the Mdm2/X-p53 interaction published from 2011 until 2012. Expert opinion: The area of small molecule Mdm2/X-p53 interaction inhibitor development is progressing fast. Several Phase I clinical studies and preclinical programs are now in progress, however, the clinical proof concept has yet to be demonstrated. Multiple available compounds inhibit Mdm2-p53 interaction with nanomolar affinities, but MdmX is still missing such potent binders. Since research points to a complementary mode of Mdm2 and MdmX action, the future compound classes will possibly want to include dual actions versus Mdm2 and MdmX

Amelioration of radiation esophagitis by orally administered p53/Mdm2/Mdm4 inhibitor (BEB55) or GS-nitroxide

Background/Aim: Esophagitis is a significant toxicity of radiation therapy for lung cancer. In this study, reduction of irradiation esophagitis in mice, by orally administered p53/Mdm2/Mdm4 inhibitor, BEB55, or the GS-nitroxide, JP4-039, was evaluated. Materials and Methods: BEB55 or JP4-039 in F15 (liposomal) formulation was administered intraesophageally to C57BL/6 mice prior to thoracic irradiation of 29 Gy x 1 or 11.5 Gy x 4 thoracic irradiation. Progenitor cells were sorted from excised esophagus, and nitroxide was quantified, by electron paramagnetic resonance (EPR). Mice with Lewis lung carcinoma (3LL) orthotopic lung tumors were treated with BEB55 or JP4-039 prior to 20 Gy to determine if the drugs would protect the tumor cells from radiation. Results: Intraesophageal BEB55 and JP4-039 compared to formulation alone increased survival after single fraction (p=0.0209 and 0.0384, respectively) and four fraction thoracic irradiation (p=0.0241 and 0.0388, respectively). JP4-039 was detected in esophagus, liver, bone marrow, and orthotopic Lewis lung carcinoma (3LL) tumor. There was no significant radiation protection of lung tumors by BEB55 or JP4-039 compared to formulation only as assessed by survival (p=0.3021 and 0.3693, respectively). Thus, BEB55 and JP4-039 safely ameliorate radiation esophagitis in mice

The effect of cell geometry and trigger method on the risks associated with thermal runaway of lithium-ion batteries

Consideration of thermal runaway heat output variability is paramount for the development of safe lithium-ion battery assemblies. This study utilizes data gathered from fractional thermal runaway calorimetry (FTRC) experiments to conduct a comparative analysis of thermal runaway heat output for three cell formats (18650, 21700, and 33600) as a function of trigger method (heaters, internal short-circuiting device, and nail penetration). The analysis is based on comparisons for the calculated total energy yield, fractional energy yield, heat rate, and heat flux. This study reveals that nail penetration tends to result in higher thermal runaway heat output for larger cells (21700 & 33600); these experiments also tended to result in higher fractions of the total energy being released through the cell body. The smaller cells (18650) did not appear to have significant variation in heat output as a function of trigger method. This finding suggests that, for this cell type, worst-case scenario heat output could be achievable in assembly level testing regardless of the utilized trigger method. This study also demonstrates successful translation of FTRC results, as recorded in the Battery Failure Databank, into meaningful analysis that breaks down the influence of specific conditions on thermal runaway heat output