Search

The purpose of this paper is to examine the long run and the short run relationship between household income gap, physical capital, human capital, and technological progress in Malaysia. Based on the Solow's growth model, this study applied the panel cointegration estimation of the full modified ordinary least square (FMOLS), as well as the Granger causality analysis. The result showed that there is a short run and long run relationship running from physical capital, human capital, technological progress towards the income gap of M40 and B40 groups of households. This study is unique because it addresses the income gap between a group of households of the bottom 40% and middle 40% across all states in Malaysia.

This study focuses on the performance of credit guarantee corporations and development financial institutions that promotes industrialisation, agricultural investment, and growth in small and medium enterprises in Malaysia. A non-parametric technique is used in this analysis to determine the scale and technical efficiency of development financial institutions since the performance of these institutions is directly reflected in the development and economic growth of the sector they promote. The empirical findings we obtained suggested that all development financial institutions are operating satisfactorily in extending their services to small and medium local enterprises.

The host kinase casein kinase 2 (CSNK2) has been proposed to be an antiviral target against β-coronaviral infection. To pharmacologically validate CSNK2 as a drug target in vivo, potent and selective CSNK2 inhibitors with good pharmacokinetic properties are required. Inhibitors based on the pyrazolo[1,5- a ]pyrimidine scaffold possess outstanding potency and selectivity for CSNK2, but bioavailability and metabolic stability are often challenging. By strategically installing a fluorine atom on an electron-rich phenyl ring of a previously characterized inhibitor 1 , we discovered compound 2 as a promising lead compound with improved in vivo metabolic stability. Compound 2 maintained excellent cellular potency against CSNK2, submicromolar antiviral potency, and favorable solubility, and was remarkably selective for CSNK2 when screened against 192 kinases across the human kinome. We additionally present a co-crystal structure to support its on-target binding mode. In vivo, compound 2 was orally bioavailable, and demonstrated modest and transient inhibition of CSNK2, although antiviral activity was not observed, possibly attributed to its lack of prolonged CSNK2 inhibition.

The pyrazolo[1,5- a ]pyrimidine scaffold is a promising scaffold to develop potent and selective CSNK2 inhibitors with antiviral activity against β-coronaviruses. Herein, we describe the discovery of a 1,2,4-triazole group to substitute a key amide group for CSNK2 binding present in many potent pyrazolo[1,5- a ]pyrimidine inhibitors. Crystallographic evidence demonstrates that the 1,2,4-triazole replaces the amide in forming key hydrogen bonds with Lys68 and a water molecule buried in the ATP-binding pocket. This isosteric replacement improves potency and metabolic stability at a cost of solubility. Optimization for potency, solubility, and metabolic stability led to the discovery of the potent and selective CSNK2 inhibitor 53 . Despite excellent in vitro metabolic stability, rapid decline in plasma concentration of 53 in vivo was observed and may be attributed to lung accumulation, although in vivo pharmacological effect was not observed. Further optimization of this novel chemotype may validate CSNK2 as an antiviral target in vivo.

Plasmodium kinases are increasingly recognized as potential novel antiplasmodial targets for the treatment of malaria, but only a small subset of these kinases have had structure-activity relationship (SAR) campaigns reported. Herein we report the discovery of CZC-54252 ( 1 ) as an inhibitor of five P. falciparum kinases PfARK1, PfARK3, PfNEK3, PfPK9, and PfPKB. 39 analogues were evaluated against all five kinases to establish SAR at three regions of the kinase active site. Nanomolar inhibitors of each kinase were discovered. We identified common and divergent SAR trends across all five kinases, highlighting substituents in each region that improve potency and selectivity for each kinase. Potent analogues were evaluated against the P. falciparum blood stage. Eight submicromolar inhibitors were discovered, of which 37 demonstrated potent antiplasmodial activity (EC 50 = 0.16 μM). Our results provide an understanding of features needed to inhibit each individual kinase and lay groundwork for future optimization efforts toward novel antimalarials., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

3-Cyano-7-cyclopropylamino-pyrazolo[1,5- a ]pyrimidines, including the chemical probe SGC-CK2-1, are potent and selective inhibitors of CSNK2A in cells but have limited utility in animal models due to their poor pharmacokinetic properties. While developing analogues with reduced intrinsic clearance and the potential for sustained exposure in mice, we discovered that phase II conjugation by GST enzymes was a major metabolic transformation in hepatocytes. A protocol for codosing with ethacrynic acid, a covalent reversible GST inhibitor, was developed to improve the exposure of analogue 2h in mice. A double codosing protocol, using a combination of ethacrynic acid and irreversible P450 inhibitor 1-aminobenzotriazole, increased the blood level of 2h by 40-fold at a 5 h time point., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

There are over 500 human kinases ranging from very well-studied to almost completely ignored. Kinases are tractable and implicated in many diseases, making them ideal targets for medicinal chemistry campaigns, but is it possible to discover a drug for each individual kinase? For every human kinase, we gathered data on their citation count, availability of chemical probes, approved and investigational drugs, PDB structures, and biochemical and cellular assays. Analysis of these factors highlights which kinase groups have a wealth of information available, and which groups still have room for progress. The data suggest a disproportionate focus on the more well characterized kinases while much of the kinome remains comparatively understudied. It is noteworthy that tool compounds for understudied kinases have already been developed, and there is still untapped potential for further development in this chemical space. Finally, this review discusses many of the different strategies employed to generate selectivity between kinases. Given the large volume of information available and the progress made over the past 20 years when it comes to drugging kinases, we believe it is possible to develop a tool compound for every human kinase. We hope this review will prove to be both a useful resource as well as inspire the discovery of a tool for every kinase., (© 2023 The Author(s).)

Pathological loss-of-function mutations in cyclin-dependent kinase-like 5 ( CDKL5 ) cause CDKL5 deficiency disorder (CDD), a rare and severe neurodevelopmental disorder associated with severe and medically refractory early-life epilepsy, motor, cognitive, visual, and autonomic disturbances in the absence of any structural brain pathology. Analysis of genetic variants in CDD has indicated that CDKL5 kinase function is central to disease pathology. CDKL5 encodes a serine-threonine kinase with significant homology to GSK3β, which has also been linked to synaptic function. Further, Cdkl5 knock-out rodents have increased GSK3β activity and often increased long-term potentiation (LTP). Thus, development of a specific CDKL5 inhibitor must be careful to exclude cross-talk with GSK3β activity. We synthesized and characterized specific, high-affinity inhibitors of CDKL5 that do not have detectable activity for GSK3β. These compounds are very soluble in water but blood-brain barrier penetration is low. In rat hippocampal brain slices, acute inhibition of CDKL5 selectively reduces postsynaptic function of AMPA-type glutamate receptors in a dose-dependent manner. Acute inhibition of CDKL5 reduces hippocampal LTP. These studies provide new tools and insights into the role of CDKL5 as a newly appreciated key kinase necessary for synaptic plasticity. Comparisons to rodent knock-out studies suggest that compensatory changes have limited the understanding of the roles of CDKL5 in synaptic physiology, plasticity, and human neuropathology., Competing Interests: AC, MS, CW, JS, CF, HO, YL, WR, JS, FB, JS, IG, KD, DD, NP, AB, SU No competing interests declared, TB Consultancy for AveXis, Ovid, GW Pharmaceuticals, International Rett Syndrome Foundation, Takeda, Taysha, CureGRIN, GRIN Therapeutics, Alcyone, Neurogene, and Marinus; Clinical Trials with Acadia, Ovid, GW Pharmaceuticals, Marinus and RSRT; all remuneration has been made to his department, AA Advisor for Proteic Bioscience Inc, (© 2023, Castano, Silvestre et al.)

Despite mediating several essential processes in the brain, including during development, cyclin-dependent kinase-like 5 (CDKL5) remains a poorly characterized human protein kinase. Accordingly, its substrates, functions, and regulatory mechanisms have not been fully described. We realized that availability of a potent and selective small molecule probe targeting CDKL5 could enable illumination of its roles in normal development as well as in diseases where it has become aberrant due to mutation. We prepared analogs of AT-7519, a compound that has advanced to phase II clinical trials and is a known inhibitor of several cyclin-dependent kinases (CDKs) and cyclin-dependent kinase-like kinases (CDKLs). We identified analog 2 as a highly potent and cell-active chemical probe for CDKL5/GSK3 (glycogen synthase kinase 3). Evaluation of its kinome-wide selectivity confirmed that analog 2 demonstrates excellent selectivity and only retains GSK3α/β affinity. We next demonstrated the inhibition of downstream CDKL5 and GSK3α/β signaling and solved a co-crystal structure of analog 2 bound to human CDKL5. A structurally similar analog ( 4 ) proved to lack CDKL5 affinity and maintain potent and selective inhibition of GSK3α/β, making it a suitable negative control. Finally, we used our chemical probe pair ( 2 and 4 ) to demonstrate that inhibition of CDKL5 and/or GSK3α/β promotes the survival of human motor neurons exposed to endoplasmic reticulum stress. We have demonstrated a neuroprotective phenotype elicited by our chemical probe pair and exemplified the utility of our compounds to characterize the role of CDKL5/GSK3 in neurons and beyond.

Bivalent chemical degraders, otherwise known as proteolysis-targeting chimeras (PROTACs), have proven to be an efficient strategy for targeting overexpressed or mutated proteins in cancer. PROTACs provide an alternative approach to small-molecule inhibitors, which are restricted by occupancy-driven pharmacology, often resulting in acquired inhibitor resistance via compensatory increases in protein expression. Despite the advantages of bivalent chemical degraders, they often have suboptimal physicochemical properties and optimization for efficient degradation remains highly unpredictable. Herein, we report the development of a potent EED-targeted PRC2 degrader, UNC7700. UNC7700 contains a unique cis -cyclobutane linker and potently degrades PRC2 components EED (DC 50 = 111 nM; D max = 84%), EZH2 WT /EZH2 Y641N (DC 50 = 275 nM; D max = 86%), and to a lesser extent SUZ12 ( D max = 44%) after 24 h in a diffuse large B-cell lymphoma DB cell line. Characterization of UNC7700 and related compounds for ternary complex formation and cellular permeability to provide a rationale for the observed improvement in degradation efficiency remained challenging. Importantly, UNC7700 dramatically reduces H3K27me3 levels and is anti-proliferative in DB cells (EC 50 = 0.79 ± 0.53 μM).

Malaria is a devastating disease that causes significant global morbidity and mortality. The rise of drug resistance against artemisinin-based combination therapy demonstrates the necessity to develop alternative antimalarials with novel mechanisms of action. We report the discovery of Ki8751 as an inhibitor of essential kinase PfPK6. 79 derivatives were designed, synthesized and evaluated for PfPK6 inhibition and antiplasmodial activity. Using group efficiency analyses, we established the importance of key groups on the scaffold consistent with a type II inhibitor pharmacophore. We highlight modifications on the tail group that contribute to antiplasmodial activity, cumulating in the discovery of compound 67, a PfPK6 inhibitor (IC 50  = 13 nM) active against the P. falciparum blood stage (EC 50  = 160 nM), and compound 79, a PfPK6 inhibitor (IC 50  < 5 nM) with dual-stage antiplasmodial activity against P. falciparum blood stage (EC 50  = 39 nM) and against P. berghei liver stage (EC 50  = 220 nM)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Introduction: The deployment of Artemisinin-based combination therapies and transmission control measures led to a decrease in the global malaria burden over the recent decades. Unfortunately, this trend is now reversing, in part due to resistance against available treatments, calling for the development of new drugs against untapped targets to prevent cross-resistance., Areas Covered: In view of their demonstrated druggability in noninfectious diseases, protein kinases represent attractive targets. Kinase-focussed antimalarial drug discovery is facilitated by the availability of kinase-targeting scaffolds and large libraries of inhibitors, as well as high-throughput phenotypic and biochemical assays. We present an overview of validated Plasmodium kinase targets and their inhibitors, and briefly discuss the potential of host cell kinases as targets for host-directed therapy., Expert Opinion: We propose priority research areas, including (i) diversification of Plasmodium kinase targets (at present most efforts focus on a very small number of targets); (ii) polypharmacology as an avenue to limit resistance (kinase inhibitors are highly suitable in this respect); and (iii) preemptive limitation of resistance through host-directed therapy (targeting host cell kinases that are required for parasite survival) and transmission-blocking through targeting sexual stage-specific kinases as a strategy to protect curative drugs from the spread of resistance.

Essential plasmodial kinases Pf GSK3 and Pf PK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual Pf GSK3/ Pf PK6 inhibitor active against blood stage Pf 3D7 parasites. To establish structure-activity relationships for Pf PK6 and Pf GSK3, 52 analogues were synthesized and assessed for the inhibition of Pf GSK3 and Pf PK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual Pf GSK3/ Pf PK6 inhibitors 23d ( Pf GSK3/ Pf PK6 IC 50 = 172/11 nM) and 23e ( Pf GSK3/ Pf PK6 IC 50 = 97/8 nM) with antiplasmodial activity ( 23d Pf 3D7 EC 50 = 552 ± 37 nM and 23e Pf 3D7 EC 50 = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual Pf PK6/ Pf GSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.

Fluorinated organoboranes serve as versatile synthetic precursors for the preparation of value-added fluorinated organic compounds. Recent progress has been mainly focused on the transition-metal catalyzed defluoroborylation. Herein, we report a photocatalytic defluoroborylation platform through direct B-H activation of N-heterocyclic carbene boranes, through the synergistic merger of a photoredox catalyst and a hydrogen atom transfer catalyst. This atom-economic and operationally simple protocol has enabled defluoroborylation of an extremely broad scope of multifluorinated substrates including polyfluoroarenes, gem-difluoroalkenes, and trifluoromethylalkenes in a highly selective fashion. Intriguingly, the defluoroborylation protocol can be transition-metal free, and the regioselectivity obtained is complementary to the reported transition-metal-catalysis in many cases., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Catalytic alkene difunctionalization via Si-H and C-H activations represents an ideal atom- and step-economic pathway for quick assembly of molecular complexity. We herein developed a visible-light-promoted metal-free difunctionalization of alkenes using abundant CO 2 and readily available Si-H and C(sp 3 )-H bonds as feedstocks. Through the merger of photoredox and hydrogen-atom-transfer catalysis, a variety of value-added compounds, such as β-silacarboxylic acids and acids bearing a γ-heteroatom (e.g., N, O, S) could be directly accessed from simple alkenes in a redox-neutral fashion., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The potential risk of an electric air hand dryer contributing to airborne infection in a hospital was investigated using a strain of Serratia marcescens and a strain of coagulase-negative, streptomycin-resistant Staphylococcus. Dispersal of marker bacteria by the air dryer was demonstrated within a radius of about 3 feet from the dryer and to the investigator's laboratory coat. When paper towels were used for hand drying, no dispersal of marker bacteria was demonstrated. It is suggested that air hand dryers are unsuitable for use in critical patient care areas as they may contribute to cross infection either via airborne dissemination or via contaminated personnel.