ABSTRACT
Kallikrein-related peptidase 6 (KLK6) is a secreted serine protease that belongs to the family of tissue kallikreins (KLKs). Many KLKs are investigated as potential biomarkers for cancer as well as therapeutic drug targets for a number of pathologies. KLK6, in particular, has been implicated in neurodegenerative diseases and cancer, but target validation has been hampered by a lack of selective inhibitors. This work introduces a class of depsipeptidic KLK6 inhibitors, discovered via high-throughput screening, which were found to function as substrate mimics that transiently acylate the catalytic serine of KLK6. Detailed structure-activity relationship studies, aided by in silico modeling, uncovered strict structural requirements for potency, stability, and acyl-enzyme complex half-life. An optimized scaffold, DKFZ-251, demonstrated good selectivity for KLK6 compared to other KLKs, and on-target activity in a cellular assay. Moreover, DKFZ-633, an inhibitor-derived activity-based probe, could be used to pull down active endogenous KLK6.
Subject(s)
Cell Proliferation/drug effects , Depsipeptides/pharmacology , Enzyme Inhibitors/pharmacology , Kallikreins/antagonists & inhibitors , Neoplasms/drug therapy , Depsipeptides/chemistry , Enzyme Inhibitors/chemistry , High-Throughput Screening Assays , Humans , Models, Molecular , Neoplasms/enzymology , Neoplasms/pathology , Protein Conformation , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Drug development faces the double challenge of increasing costs and increasing pressure on pricing. To avoid that lack of perceived commercial perspective will leave existing medical needs unmet, pharmaceutical companies and many other stakeholders are discussing ways to improve the efficiency of drug Research and Development. Based on an international symposium organized by the Medical School of the University of Duisburg-Essen (Germany) and held in January 2016, we discuss the opportunities and challenges of three specific areas, i.e., public-private partnerships, adaptive designs and big data. Public-private partnerships come in many different forms with regard to scope, duration and type and number of participants. They range from project-specific collaborations to strategic alliances to large multi-party consortia. Each of them offers specific opportunities and faces distinct challenges. Among types of collaboration, investigator-initiated studies are becoming increasingly popular but have legal, ethical, and financial implications. Adaptive trial designs are also increasingly discussed. However, adaptive should not be used as euphemism for the repurposing of a failed trial; rather it requires carefully planning and specification before a trial starts. Adaptive licensing can be a counter-part of adaptive trial design. The use of Big Data is another opportunity to leverage existing information into knowledge useable for drug discovery and development. Respecting limitations of informed consent and privacy is a key challenge in the use of Big Data. Speakers and participants at the symposium were convinced that appropriate use of the above new options may indeed help to increase the efficiency of future drug development.
ABSTRACT
The absolute configuration has been determined for the title compound, C(14)H(20)N(2)OS. Inter-molecular N-Hâ¯O hydrogen bonds are observed in the crystal packing, forming infinitive one-dimensional chains with the base vector [100].
ABSTRACT
The absolute configuration has been determined for the title compound, C(14)H(20)N(2)OS. There are two independent mol-ecules in the asymmetric unit. Inter-molecular N-Hâ¯O hydrogen bonds are observed in the crystal packing, forming infinite chains with the base vectors [100] and [010]. Each chain contains only one of the two independent mol-ecules.
ABSTRACT
[Objective]A modified femoral resection method Was introduced for total knee replacement,by which the resection ofthe posterior femoral condyle was increased.This study is to verify the accuracy of resection.[Methods]In 81 knees undergoingtotal knee replacement,the thickness of vKrious cuts were measured and compared with the height of the implants.The mean val-ues of these measurements were calculated,and eompqrisons were made according to the mechanical axis using Student's t-test.[Results]On average,the thickness of bone resection in both the flexion and the extension gap was smaller than the thickness otthe prosthesis.In the varus group a minimum lateral over-resection in the flexion gap Was found,and in valgus group a minimummedial over-resection in the flexion gap was found.[Conclusion]The early clinical results with this modified resection method aregood.
ABSTRACT
The synthesis and structure of [{MgCl(thf)2}3(mu3-C3H5)2]2[Mg(C3H5)4], which contains both a cationic cluster Grignard and a tetraorganomagnesiate dianion, are reported.
ABSTRACT
Objective To modify femoral resection method in primary total knee arthroplasty and verify the operative results of this modification through measurement of the thickness of the bone resection and clinical follow up. Methods The femoral resection measurement guide was modified so that the resection of the posterior femoral condyle was increased 3 mm in thickness. A total of 81 cases undergoing total knee replacement were divided into varus group and valgus group, in which the thickness of various resections were measured and compared with that of the prosthetic implants. The average follow-up time was 27.1 months. Results On average, the thickness of bone resection in both the flexion and the extension gaps was smaller than that of the prosthesis. In both groups, except for the thickness of the posterior femoral condyle, there were significant differences in other indices ( P
