Discovery of Ligands for TRIM58, a Novel Tissue-Selective E3 Ligase.

Redirecting E3 ligases to neo-substrates, leading to their proteasomal disassembly, known as targeted protein degradation (TPD), has emerged as a promising alternative to traditional, occupancy-driven pharmacology. Although the field has expanded tremendously over the past years, the choice of E3 ligases remains limited, with an almost exclusive focus on CRBN and VHL. Here, we report the discovery of novel ligands to the PRY-SPRY domain of TRIM58, a RING ligase that is specifically expressed in erythroid precursor cells. A DSF screen, followed by validation using additional biophysical methods, led to the identification of TRIM58 ligand TRIM-473. A basic SAR around the chemotype was established by utilizing a competitive binding assay employing a short FP peptide probe derived from an endogenous TRIM58 substrate. The X-ray co-crystal structure of TRIM58 in complex with TRIM-473 gave insights into the binding mode and potential exit vectors for bifunctional degrader design.

Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker. However, the resulting ADCs lacked antigen-specificity in vivo, probably from premature release of the payload. Second-generation ADCs were then developed, using noncleavable linkers, and the resulting conjugates (ADC-4 and ADC-10) led to in vivo efficacy in an HER-2 expressing (SK-OV-3ip) mouse xenograft model while ADC-11 led to in vivo efficacy in an anti-c-KIT (NCI-H526) mouse xenograft model in a target-dependent manner.

Natural product drug delivery: A special challenge?

Natural products have a long-standing and critical role in drug development and medical use. The structural and physicochemical properties of natural products, while derived evolutionarily to be effective in living systems, may create challenges in translation to a pharmaceutical product. Molecular complexity, low solubility, functional group reactivity and general instability are among the challenges that typically need to be overcome. This review looks at some of the ways that natural products have been formulated and delivered to enable the successful application of these vitally important medicines to patients.

Assessing Private and Public Need for Uniqueness: Validation of French Versions of the Need for Uniqueness (NfU) and Self-Attributed Need for Uniqueness (SANU) Scales.

Need for uniqueness represents the need for people to feel different and distinguish themselves from others. Two major scales exist that measure this need: the Need for Uniqueness scale (NfU; Snyder & Fromkin, 1977 ) and the Self-Attributed Need for Uniqueness scale (SANU; Lynn & Harris, 1997b ). We propose here a French version of both scales. Through a dual approach of exploratory and confirmatory factorial analyses, we investigated the scales' structure in student samples from two French-speaking countries (France and Switzerland, N = 1,348) as well as measures of internal and external validity. Both scales presented good psychometric properties in French. Additionally, we investigated differences between the scales, as literature suggests that the NfU relies mostly on public and risky displays of uniqueness, whereas the SANU focuses on private and more socially acceptable means to acquire a feeling of uniqueness. Differences arose in the links with several personality characteristics (emotionality, extraversion, agreeableness, sensation seeking, and self-consciousness), suggesting that the NfU corresponds rather to a need to demonstrate uniqueness through public displays and the SANU to a need to feel unique through more private means. We discuss implications for research and provide advice on choosing by the scale most appropriate to the researcher's aims.

Performance-based everyday functional competence measures across the adult lifespan: the role of cognitive abilities.

BACKGROUND: The effects of age on the ability to manage everyday functioning, crucial to ensure a healthy aging process, have been rarely examined and when, self-report measures have been used. The aim of the present study was to examine age effects across the adult lifespan in everyday functioning with two performance-based measures: the Everyday Problems Test (EPT), and the Timed Instrumental Activities of Daily Living (TIADL) tasks. The role of some crucial cognitive abilities, i.e. working memory (WM), processing speed, reasoning, vocabulary, and text comprehension in the EPT and the TIADL were also assessed to see whether or not they have a similar influence (and to what extent) in accounting for age-related effects in these two performance-based measures. METHOD: Two hundred and seventy-six healthy participants, from 40 to 89 years of age were presented with the EPT, the TIADL, as well as WM, processing speed, reasoning, text comprehension, and vocabulary tasks. RESULTS: Path models indicated an indirect effect of age and education on the EPT, which was mediated by all the cognitive variables considered, with WM and reasoning being the strongest predictors of performance. An indirect quadratic effect of age, but not of education, was found on the TIADL score, and an accelerated decline in processing speed mediated the relationship between age and the TIADL score. CONCLUSION: This study revealed age-related effects in performance-based measures, which are mediated by different cognitive abilities depending on the measure considered. The findings highlight the importance of assessing everyday functioning even in healthy older adults.