119 research outputs found
New insights into 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNI3K)
No full textWe report the synthesis of several related 4-anilinoquinazolines as inhibitors of cardiac troponin I-interacting kinase (TNNi3K). These close structural analogs of 3-((6,7-dimethoxyquinazolin-4-yl)amino)-4-(dimethylamino)-N-methylbenzenesulfonamide (GSK114) provide new understanding of structure-activity relationships between the 4-anilinoquinazoline scaffold and TNNi3K inhibition. Through a small focused library of inhibitors, we observed that the N-methylbenzenesulfonamide was driving the potency in addition to the more traditional quinazoline hinge-binding motif. We also identified a compound devoid of TNNi3K kinase activity due to the addition of a methyl group in the hinge binding region. This compound could serve as a negative control in the study of TNNi3K biology. Small molecule crystal structures of several quinazolines have been solved, supporting observations made about overall conformation and TNNi3K inhibition.</p
Targeting the water network in cyclin G-associated kinase (GAK) with 4-anilino-quin(az)oline inhibitor
No full textWater networks within kinase inhibitor design and more widely within drug discovery are generally poorly understood. The successful targeting of these networks prospectively has great promise for all facets of inhibitor design, including potency and selectivity for the target. Herein, we describe the design and testing of a targeted library of 4‐anilinoquin(az)olines for use as inhibitors of cyclin G‐associated kinase (GAK). GAK cellular target engagement assays, ATP binding‐site modelling and extensive water mapping provide a clear route to access potent inhibitors for GAK and beyond
DS_773045 – Supplemental material for Application of Integrated Drug Screening/Kinome Analysis to Identify Inhibitors of Gemcitabine-Resistant Pancreatic Cancer Cell Growth
No full textSupplemental material, DS_773045 for Application of Integrated Drug Screening/Kinome Analysis to Identify Inhibitors of Gemcitabine-Resistant Pancreatic Cancer Cell Growth by Linas J. Krulikas, Ian M. McDonald, Benjamin Lee, Denis O. Okumu, Michael P. East, Thomas S. K. Gilbert, Laura E. Herring, Brian T. Golitz, Carrow I. Wells, Allison D. Axtman, William J. Zuercher, Timothy M. Willson, Dmitri Kireev, Jen Jen Yeh, Gary L. Johnson, Antonio T. Baines, and Lee M. Graves in SLAS Discovery</p
Design and analysis of the 4-anilinoquin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure-activity relationships
No full textThe 4-anilinoquinoline and 4-anilinoquinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems, while originally designed for specific targets including epidermal growth factor receptor (EGFR), but actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4-anilinoquin(az)olines in order to better understand the structure-activity relationships of three main collateral kinase targets of quin(az)oline-based kinase inhibitors: cyclin G associated kinase (GAK), STE20-like serine/threonine-protein kinase (SLK) and serine/threonine-protein kinase 10 (STK10). This was achieved through a series of quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites and extensive small-molecule X-ray structural analysis.</p
Synthesis and Evaluation of Novel A-Site Ligands for 2D Perovskites for Use in Studying Charge and Energy Transfer in Quantum-Confined Systems
No full textIn recent years, 3D perovskites have become the focus of many research studies, given their unique charge transfer and electronic properties. Perovskites have been
used to synthesize thin film organic solar cells, and their certified efficiencies now exceed that of multicrystalline Si. However, very little research has been conducted
into 2D perovskites, which can provide insight into charge and energy transfers that occur in quantum-confined systems. Specifically, 2D perovskites have a large
interfacial volume, which could allow for charge and energy transfer to occur via resonance, intersystem crossing, and exciton-charge interactions. Exciton-charge
interactions in particular have proved problematic in organic LEDs, and 2D perovskites would theoretically allow us to obviate this issue. Studying these would require creating alternating layers of organic molecules and inorganic perovskites in order to focus on quantum wells. Synthesizing 2D perovskites requires a specific type of A-site ligand, as they need to be heavily conjugated and contain linker chains. At the same time, we need to make sure we control the exciton binding energy and that the ligands can bind to the octahedral inorganic perovskites. This thesis examines the synthesis of novel A-site ligands for 2D perovskites and characterizes the effectiveness of their charge transfer properties. The effectiveness characterization is done in conjunction with Prof. Barry Rand’s group in the Electrical Engineering Department. In addition, this thesis contains a chapter analyzing the cost-effectiveness of perovskites, specifically the cost of procuring metals for use in 3D and 2D perovskites and comparing this cost to existing materials used in LEDs and organic solar cells. This thesis will also examine the future financial outlook for perovskites and attempt to determine cost-effective commercial opportunities based on current economic trends
Identification and optimization of 4-anilinoquinolines as inhibitors of cyclin G associated kinase
No full text4-Anilinoquinolines were identified as potent and narrow-spectrum inhibitors of the cyclin G associated kinase (GAK), an important regulator of viral and bacterial entry into host cells. Optimization of the 4-anilino group and the 6,7-quinoline substituents produced GAK inhibitors with nanomolar activity, over 50 000-fold selectivity relative to other members of the numb-associated kinase (NAK) subfamily, and a compound (6,7-dimethoxy-N-(3,4,5-trimethoxyphenyl)quinolin-4-amine; 49) with a narrow-spectrum kinome profile. These compounds may be useful tools to explore the therapeutic potential of GAK in prevention of a broad range of infectious and systemic diseases
Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships
No full textThe oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off-target kinase. The oxindole has long been considered a promiscuous kinase inhibitor template, but across these four specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different ranging from narrow to broad spectrum kinome coverage. We synthesized a large series of analogues, utilizing quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, kinome profiling, and small-molecule x-ray structural analysis to optimize TLK2 inhibition and kinome selectivity. This resulted in the identification of several narrow spectrum, sub-family selective, chemical tool compounds including 128 (UNC-CA2-103) that could enable elucidation of TLK2 biology.</p
Extreme Open Science: Companies Sharing Compounds without Restriction
No full textAlthough the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. We describe how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. As a result, new drug targets were identified and the science of kinase chemogenomics was established
Extreme Open Science: Companies Sharing Compounds without Restriction
No full textAlthough the human genome provides the blueprint for life, most of the proteins it encodes remain poorly studied. We describe how one group of scientists, in seeking new targets for drug discovery, used open science through unrestricted sharing of small molecules to shed light on dark matter of the genome. Starting initially with a single pharmaceutical company before expanding to multiple companies, a precedent was established for sharing published kinase inhibitors as chemical tools. As a result, new drug targets were identified and the science of kinase chemogenomics was established
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