Models for protein assembly in the prion diseases

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 1994.Includes bibliographical references.by Jon H. Come.Ph.D

A Three-Hybrid Approach to Scanning the Proteome for Targets of Small Molecule Kinase Inhibitors

AbstractIn this study, we explored the application of a yeast three-hybrid (Y3H)-based compound/protein display system to scanning the proteome for targets of kinase inhibitors. Various known cyclin-dependent kinase (CDK) inhibitors, including purine and indenopyrazole analogs, were displayed in the form of methotrexate-based hybrid ligands and deployed in cDNA library or yeast cell array-based screening formats. For all inhibitors, known cell cycle CDKs as well as novel candidate CDK-like and/or CDK-unrelated kinase targets could be identified, many of which were independently confirmed using secondary enzyme assays and affinity chromatography. The Y3H system described here may prove generally useful in the discovery of candidate drug targets

Mechanistic and Preparative Studies of the Intramolecular Photocyclization of Methylated 2-(4-Pentenyl) Tropones

Irradiation of various methylated 2-(4-pentenyl)tropones affords regioisomeric formal[6π+2πand[87π + 2π]cycloadducts. The cyclooctadiene-containing [6π + 2π]adductsare produced as mixtures of stereoisomers. A self-consistent mechanistic scheme based upon evidence accumulated through the study of regioselectivity and stereoselectivity as a function of reaction conditions has been proposed. This mechanism includes several discrete intermediates en route to the final cycloadducts. Attempts to functionalize [6π + 2π] cycloadducts through vinyllithium addition led to unconventional products through unanticipated reaction pathways

Clinical applications of allografts in foot and ankle surgery

Purpose: The purpose of this review is to systematically analyse current literature on the use of allografts in the surgical treatment of foot and ankle disorders in adult patients. Based on this study, we propose evidence-based recommendations. Methods: The database for PubMed was searched for all published articles. No timeframe restrictions were applied. Clinical studies eligible for inclusion met the following criteria: performed on patients over 18 years old; subject to surgical treatment of foot and ankle disorders; with report on the outcome of the use of allografts; with a report and assessment of pain and function, or equivalent; minimum follow-up of 1 year was required. Two reviewers independently screened and selected studies for full-text analysis from title and abstract. 107 studies were included from 1113 records. Studies were grouped according to surgical indications into ten categories: musculoskeletal tumours (n = 16), chronic ankle instability (n = 15), ankle arthritis (n = 14), osteochondral lesions of the talus (n = 12), Achilles tendon defects (n = 11), other tendon defects (n = 9), fusions (n = 9), fractures (n = 8), hallux rigidus (n = 3) and other indications (n = 10). Results: Most studies displayed evidence level of IV (n = 57) and V (n = 39). There was one level I, one level II and nine level III studies. Most studies reported allografting as a good option (n = 99; 92.5%). Overall complication rate was 17% (n = 202). Conclusions: Fair evidence (Grade B) was found in favour of the use of allografts in lateral ankle ligament reconstruction or treatment of intra-articular calcaneal fracture. Fair evidence (Grade B) was found against the use of allogeneic MSCs in tibiotalar fusions. Level of evidence: V

Discovery of Highly Isoform Selective Thiazolopiperidine Inhibitors of Phosphoinositide 3‑Kinase γ

A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3‑Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of <b>16</b>, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis

Design and Synthesis of a Novel Series of Orally Bioavailable, CNS-Penetrant, Isoform Selective Phosphoinositide 3‑Kinase γ (PI3Kγ) Inhibitors with Potential for the Treatment of Multiple Sclerosis (MS)

The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of <b>16</b>, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis