Systematic Investigation of the Permeability of Androgen Receptor PROTACs

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed

The internal structure and composition of a plate-boundary-scale serpentinite shear zone: the Livingstone Fault, New Zealand

Abstract. Deciphering the internal structure and composition of large serpentinite-dominated shear zones will lead to an improved understanding of the rheology of the lithosphere in a range of tectonic settings. The Livingstone Fault in New Zealand is a terrane-bounding structure that separates the basal portions (peridotite; serpentinised peridotite; metagabbros) of the Dun Mountain Ophiolite Belt from the quartzofeldspathic schists of the Caples and Aspiring Terrane. Field and microstructural observations from 11 localities along a strike length of ca. 140 km show that the Livingstone Fault is a steeply dipping, serpentinite-dominated shear zone tens of metres to several hundred metres wide. The bulk shear zone has a pervasive scaly fabric that wraps around fractured and faulted pods of massive serpentinite, rodingite and partially metasomatised quartzofeldspathic schist up to a few tens of metres long. S–C fabrics and lineations in the shear zone consistently indicate a steep east-side-up shear sense, with significant local dispersion in kinematics where the shear zone fabrics wrap around pods. The scaly fabric is dominated (>98 % vol) by fine-grained (≪10 µm) fibrous chrysotile and lizardite–polygonal serpentine, but infrequent (<1 % vol) lenticular relicts of antigorite are also preserved. Dissolution seams and foliation surfaces enriched in magnetite, as well as the widespread growth of fibrous chrysotile in veins and around porphyroclasts, suggest that bulk shear zone deformation involved pressure–solution. Syn-kinematic metasomatic reactions occurred along all boundaries between serpentinite, schist and rodingite, forming multigenerational networks of nephritic tremolite veins that are interpreted to have caused reaction hardening within metasomatised portions of the shear zone. We propose a conceptual model for plate-boundary-scale serpentinite shear zones which involves bulk-distributed deformation by pressure–solution creep, accompanied by a range of physical (e.g. faulting in pods and wall rocks; smearing of magnetite along fault surfaces) or chemical (e.g. metasomatism) processes that result in localised brittle deformation within creeping shear zone segments

Systematic Investigation of the Permeability of Androgen Receptor PROTACs.

Bifunctional molecules known as PROTACs simultaneously bind an E3 ligase and a protein of interest to direct ubiquitination and clearance of that protein, and they have emerged in the past decade as an exciting new paradigm in drug discovery. In order to investigate the permeability and properties of these large molecules, we synthesized two panels of PROTAC molecules, constructed from a range of protein-target ligands, linkers, and E3 ligase ligands. The androgen receptor, which is a well-studied protein in the PROTAC field was used as a model system. The physicochemical properties and permeability of PROTACs are discussed.This work was funded by Alzheimer’s Research UK (grant: ARUK-2015DDI-CAM), with support from the ALBORADA Trust. The ALBORADA Drug Discovery Institute is core funded by Alzheimer’s Research UK (registered charity No. 1077089 and SC042474)

Defective DNA Repair and Increased Genomic Instability in Artemis-deficient Murine Cells

In developing lymphocytes, the recombination activating gene endonuclease cleaves DNA between V, D, or J coding and recombination signal (RS) sequences to form hairpin coding and blunt RS ends, which are fused to form coding and RS joins. Nonhomologous end joining (NHEJ) factors repair DNA double strand breaks including those induced during VDJ recombination. Human radiosensitive severe combined immunodeficiency results from lack of Artemis function, an NHEJ factor with in vitro endonuclease/exonuclease activities. We inactivated Artemis in murine embryonic stem (ES) cells by targeted mutation. Artemis deficiency results in impaired VDJ coding, but not RS, end joining. In addition, Artemis-deficient ES cells are sensitive to a radiomimetic drug, but less sensitive to ionizing radiation. VDJ coding joins from Artemis-deficient ES cells, which surprisingly are distinct from the highly deleted joins consistently obtained from DNA-dependent protein kinase catalytic subunit–deficient ES cells, frequently lack deletions and often display large junctional palindromes, consistent with a hairpin coding end opening defect. Strikingly, Artemis-deficient ES cells have increased chromosomal instability including telomeric fusions. Thus, Artemis appears to be required for a subset of NHEJ reactions that require end processing. Moreover, Artemis functions as a genomic caretaker, most notably in prevention of translocations and telomeric fusions. As Artemis deficiency is compatible with human life, Artemis may also suppress genomic instability in humans