Achieving effective and selective CK1 inhibitors through structure modification

Casein kinase 1 (CK1) is an extensively expressed serine/threonine kinase family, with six highly conserved isoforms of human CK1. Due to its involvement in many biological processes, CK1 is a promising target for several pathological states, including circadian sleep disorder, neurodegenerative diseases, cancer and inflammation. However, due to the structural similarities between the six CK1 members, the design of CK1 inhibitors is intricate. So far, no effective CK1 inhibitors are reported to reach clinical trials; thus, approaches to obtaining both selective and effective CK1 inhibitors are in great demand. Here we analyze several CK1 inhibitors that provide successful experience for structure-based drug design and rational structure modification, which could provide references for further drug design.

Download Full-text

Arabidopsis MLK3, a Plant-specific Casein Kinase 1, Negatively Regulated Flowering and Phosphorylated Histone H3 in vivo

10.21203/rs.2.16145/v1 ◽

2019 ◽

Author(s):

Zhen Wang ◽

Junmei Kang ◽

Shangang Jia ◽

Tiejun Zhang ◽

Zhihai Wu ◽

...

Keyword(s):

Kinase Activity ◽

Histone H3 ◽

Casein Kinase ◽

Kinase Assay ◽

Wild Type ◽

Serine Threonine Kinase ◽

Altered Expression ◽

Casein Kinase 1 ◽

Threonine Kinase

Abstract Background: Casein kinase 1 (CK1) family members are highly conserved serine/threonine kinase present in most eukaryotes with multiple biological functions. Arabidopsis MUT9-like kinases ( MLKs ) belong to a clade CK1 specific to the plant kingdom and have been implicated collectively in modulating flowering related processes. Three of the four MLKs ( MLK1/2/4 ) have been characterized, however, little is known about MLK3 , the most divergent MLKs. Results: We demonstrated that compared with wild type, mlk3 , a truncated MLK3 , flowered slightly early under long day conditions and ectopic expression of MLK3 rescued the morphological defects of mlk3 , indicating that MLK3 negatively regulates flowering. GA 3 application accelerated flowering of both wild type and mlk3 , suggesting that mlk3 had normal GA response. The recombinant MLK3-GFP was localized in the nucleus exclusively. In vitro kinase assay revealed that the nuclear protein MLK3 phosphorylated histone 3 at threonine 3 (H3T3ph). Mutation of a conserved catalytic residue (Lysine 175) abolished the kinase activity and resulted in failure to complement the early flowering phenotype of mlk3 . Interestingly, the global level of H3T3 phosphorylation in mlk3 did not differ significantly from wild type, suggesting the redundant roles of MLKs in flowering regulation. The transcriptomic analysis demonstrated that 425 genes significantly altered expression level in mlk3 relative to wild type. The mlk3 mlk4 double mutant generated by crossing mlk3 with mlk4 , a loss-of-function mutant of MLK4 showing late flowering, flowered between the two parental lines, suggesting that MLK3 played an antagonistic role to MLK4 in plant transition to flowering. Conclusions: A serine/threonine kinase encoding gene MLK3 is a casein kinase 1 specific to the plant species and represses flowering slightly. MLK3 located in nucleus catalyzes the phosphorylation of histone H3 at threonine 3 in vitro and an intact lysine residue (K175) is indispensible for the kinase activity. This study sheds new light on the delicate control of flowering by the plant-specific CK1 in Arabidopsis.

Download Full-text

Targeting NAMPT for Therapeutic Intervention in Cancer and Inflammation: Structure-Based Drug Design and Biological Screening

Chemical Biology & Drug Design ◽

10.1111/cbdd.12562 ◽

2015 ◽

Vol 86 (4) ◽

pp. 881-894 ◽

Cited By ~ 5

Author(s):

Venkat K. Pulla ◽

Dinavahi S. Sriram ◽

Vijay Soni ◽

Srikant Viswanadha ◽

Dharmarajan Sriram ◽

...

Keyword(s):

Drug Design ◽

Therapeutic Intervention ◽

Biological Screening ◽

Structure Based Drug Design ◽

Cancer And Inflammation

Download Full-text

Structure-based inhibitor design and repurposing clinical drugs to target SARS-CoV-2 proteases

Biochemical Society Transactions ◽

10.1042/bst20211180 ◽

2022 ◽

Author(s):

Anoop Narayanan ◽

Shay A. Toner ◽

Joyce Jose

Keyword(s):

Drug Design ◽

Protease Inhibitors ◽

Drug Repurposing ◽

Inhibitor Design ◽

Rational Structure ◽

Structure Based Drug Design ◽

Drug Designing ◽

Clinical Drugs

SARS-CoV-2, the coronavirus responsible for the current COVID-19 pandemic, encodes two proteases, 3CLpro and PLpro, two of the main antiviral research targets. Here we provide an overview of the structures and functions of 3CLpro and PLpro and examine strategies of structure-based drug designing and drug repurposing against these proteases. Rational structure-based drug design enables the generation of potent and target-specific antivirals. Drug repurposing offers an attractive prospect with an accelerated turnaround. Thus far, several protease inhibitors have been identified, and some candidates are undergoing trials that may well prove to be effective antivirals against SARS-CoV-2.

Download Full-text

Insight into the selective inhibition of JNK family members through structure-based drug design

MedChemComm ◽

10.1039/c5md00562k ◽

2016 ◽

Vol 7 (4) ◽

pp. 686-692

Author(s):

A. Messoussi ◽

G. Chevé ◽

K. Bougrin ◽

A. Yasri

Keyword(s):

Protein Kinase ◽

Drug Design ◽

Neurodegenerative Disorders ◽

Family Members ◽

Selective Inhibition ◽

Mitogen Activated Protein Kinase ◽

Biological Processes ◽

Structure Based Drug Design ◽

Mitogen Activated Protein ◽

Insight Into

The c-Jun N-terminal kinase (JNK) family, which comprises JNK1, JNK2 and JNK3, belongs to the mitogen-activated protein kinase (MAPK) superfamily, whose members regulate myriad biological processes, including those implicated in tumorigenesis and neurodegenerative disorders.

Download Full-text

Casein kinase-1γ1 and 3 stimulate tumor necrosis factor-induced necroptosis through RIPK3

Cell Death and Disease ◽

10.1038/s41419-019-2146-4 ◽

2019 ◽

Vol 10 (12) ◽

Cited By ~ 3

Author(s):

Song-Yi Lee ◽

Hyunjoo Kim ◽

Cathena Meiling Li ◽

Jaemin Kang ◽

Ayaz Najafov ◽

...

Keyword(s):

Ectopic Expression ◽

Specific Inhibitor ◽

Casein Kinase ◽

In Vitro Assays ◽

Serine Threonine Kinase ◽

Casein Kinase 1 ◽

Threonine Kinase ◽

Necrosis Factor

AbstractUpon necroptosis activation, receptor interacting serine/threonine kinase (RIPK)1 and RIPK3 form a necrosome complex with pseudokinase mixed lineage kinase-like (MLKL). Although protein phosphorylation is a key event for RIPK1 and RIPK3 activation in response to a necroptosis signal, relatively little is known about other factors that might regulate the activity of these kinases or necrosome formation. Through a gain-of-function screen with 546 kinases and 127 phosphatases, we identified casein kinase 1 gamma (CK1γ) as a candidate necroptosis-promoting factor. Here, we show that the decreased activity or amounts of CK1γ1 and CK1γ3, either by treatment with a chemical inhibitor or knockdown in cells, reduced TNFα-induced necroptosis. Conversely, ectopic expression of CK1γ1 or CK1γ3 exacerbated necroptosis, but not apoptosis. Similar to RIPK1 and RIPK3, CK1γ1 was also cleaved at Asp343 by caspase-8 during apoptosis. CK1γ1 and CK1γ3 formed a protein complex and were recruited to the necrosome harboring RIPK1, RIPK3 and MLKL. In particular, an autophosphorylated form of CK1γ3 at Ser344/345 was detected in the necrosome and was required to mediate the necroptosis. In addition, in vitro assays with purified proteins showed that CK1γ phosphorylated RIPK3, affecting its activity, and in vivo assays showed that the CK1γ-specific inhibitor Gi prevented abrupt death in mice with hypothermia in a model of TNFα-induced systemic inflammatory response syndrome. Collectively, these data suggest that CK1γ1 and CK1γ3 are required for TNFα-induced necroptosis likely by regulating RIPK3.

Download Full-text