May 22, 2022

Medical Trend

Medical News and Medical Resources

Targets of Circadian Rhythm and Progress in Drug Development

Targets of Circadian Rhythm and Progress in Drug Development

 

Targets of Circadian Rhythm and Progress in Drug Development.  Circadian clock (also known as circadian clock) is an internal mechanism by which organisms adapt to the periodic changes of environmental factors such as light and temperature in the course of evolution. The biological clock of mammals is composed of the main biological clock and the peripheral biological clock.

The main biological clock is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. It is the pacemaker of the circadian rhythm and coordinates the cell oscillator of the whole body through nerve and hormone signals. The peripheral circadian clock is distributed in various tissues and organs, such as liver, kidney, heart, and muscle, with a certain degree of independence.

Targets of Circadian Rhythm and Progress in Drug Development

At the molecular level, the biological clock is composed of a transcription and translation feedback loop containing a variety of genes and proteins, including a core loop and a secondary stable loop, which generates and maintains the circadian rhythm of gene transcription. In the morning, CLOCK (Circadian locomotor output cycles kaput) and BMAL1 (Brain and muscle ARNT-like 1) in the core loop form a heterodimer, bind to the E-box element, and drive the expression of PER and CRY genes.

Subsequently, PER and CRY protein form an inhibitory complex, which inhibits the transactivation of CLOCK and BMAL1. The stability of PER and CRY proteins is regulated by the parallel E3 ubiquitin ligase pathway. At night, the nuclear receptor subfamily REV-ERBα and REV-ERBβ in the secondary stabilization loop act as repressors and compete with the orphan receptors (RORα, RORβ, and RORγ) associated with RAR as activators to bind to ROR/REV- The ERB response element (RORE) promoter element antagonistically regulates the expression of BMAL1 and other target genes.

In addition, D-box is also an important circadian rhythm promoter element, which can be activated by PAR-bZIP protein or inhibited by E4BP4 protein, respectively. In addition, the circadian rhythm is also regulated by post-translational modifications such as phosphorylation, ubiquitination, and acetylation.

Targets of Circadian Rhythm and Progress in Drug Development

Circadian rhythm disorders (caused by insufficient sleep, jet lag, shift work, or overnutrition, etc.) may have short-term or long-term adverse effects on health, and are related to sleep disorders, cardiovascular diseases, metabolic syndrome, autoimmune diseases, and cancer. The function of circadian rhythm also declines with age, which is related to neurodegenerative diseases. Therefore, small-molecule modulators of the circadian clock (SMMCC) target core or non-core circadian clock proteins to regulate the circadian rhythm, which has important potential in the treatment of circadian clock-related diseases, and can also increase the impact on the circadian clock system. Molecular understanding.


Table 1. Small molecule modulators targeting core clock proteins

Small molecule modulatorMechanism of actionPharmacological action
CLOCK
CLK8Inhibit the dimerization of CLOCK and BMAL1 and increase the amplitude of circadian rhythmNA
CRY1/CRY2
KL001 and stable CRY derivatives (SHP656, KL101 and TH301)Stabilize CRY, prolong the circadian rhythm, inhibit Bmal1 amplitudeImprove the glucose tolerance of obese mice, inhibit the proliferation of glioblastoma stem cells, inhibit the growth of glioblastoma in vitro, and enhance the differentiation of brown adipocytes in vivo
KS15Inhibit CRY, enhance E-box-mediated transcription, inhibit circadian rhythm amplitudeInhibit the growth of breast cancer cells
REV-ERB
GSK4112Enhance the interaction between REV-ERB and NCOR peptideInhibition of gluconeogenesis and inflammation in primary cells
SR9009 and SR9011GSK4112 derivative is a selective agonist of REV-ERB, which can change the circadian rhythm behavior, the expression of biological clock genes (BMAL1, PER1 and PER 2) and the expression of some glioblastoma stem cell markers (such as OLIG2 and SOX2) Improve glucose homeostasis in obese mice, promote wakefulness, anti-anxiety, and inhibit the proliferation of glioblastoma stem cells
SR8278Antagonists derived from GSK4112 can increase the expression of REV-ERB target genes in cells (such as BMAL1, PCK1 and G6PC1)Reduce anxiety and improve myocardial damage
ROR
NobiletinAgonist, enhances the amplitude and prolongs the circadian cycleImprove the metabolic homeostasis of obese and diabetic mice, and have a wide range of effects on inflammation and atherosclerosis
NeoruscogeninAgonist, promote the interaction between ROR and NCOA2/TIF2, enhance the expression of BMAL1Activate the expression of liver ROR metabolic target genes
SR1001T0901317 derivative, with high inverse agonist activity and selectivity for RORα and RORγtInhibit Th17 cell differentiation and autoimmunity
SR2211, SR1555, digoxin, ursolic acid and ML209RORγ inverse agonistInhibit Th17 cell differentiation
SR3335RORα inverse agonistReduce blood sugar levels in obese mice
SR1078RORα agonistInduce apoptosis and inhibit the growth of liver cancer cells
RUVBL2
CordycepinInhibit the interaction of BMAL1 and RUVBL2Improve jet lag in mice

Table 2. Small molecule regulators targeting non-core clock proteins

Small molecule modulatorMechanism of actionPharmacological action
CK1/2
CKI-7, IC261, D4476, PF-670462, PF-4800567, longdaysin, LH846, compound 1-3, etc.Inhibitor, prolong the circadian cycleInhibition of CK1 can significantly prolong the circadian rhythm. CK1 is widely involved in various pathophysiological processes, including familial sleep and mood disorders
PDE4 and MAPK
RolipramPDE4 selective inhibitorNA
U0126MEK specific inhibitorNA
AMPK
MetforminAMPK agonist, interferes with the expression pattern of circadian clock genes and metabolic genesType 2 diabetes drugs
GSK3β
lithiumGSK3β inhibitor. GSK3β can phosphorylate CLOCK, PER, REV-ERBα and CRY proteinsTreatment of bipolar disorder related to circadian rhythm disorders
ADORA2B
BAY 60-6583ADORA2B agonist, stabilize PER2Enhance adenosine signal transduction and have cardioprotective effects against myocardial ischemia
CDK
Indirubin-3’-oxime、Kenpaullone、Roscovitine和Puralanol ACDK inhibitor, prolong the circadian cycleNA
BALL
Camptothecin and HarmineTOPI inhibitor, prolong the circadian cycleNA
melt
Etoposide、Mitoxantrone和AmsacrineTOPII inhibitor, shorten the circadian cycleNA
SIRT1
SRT2183 and SRT1720SIRT1 agonist, reduces circadian rhythm gene expressionNA
SRTCD1023 and SERTCL1015SIRT1 agonist, prolongs the circadian cycle and reduces the amplitudeNA
IS
17β-estradiolShorten the circadian cycleNA
PPAR RAR and RXR
RosiglitazonePPARγ agonist, enhance BMAL1 expression, regulate cardiovascular rhythmNA

 

Circadian rhythm plays an important role in drug development and clinical treatment. Time therapy is based on the biological clock, that is, to determine the appropriate administration time within the precise circadian rhythm time window to obtain better pharmacokinetic properties, improve drug efficacy, and reduce toxicity related to drug metabolism. Related cardiovascular diseases (such as hypertension, etc.) and autoimmune diseases (such as rheumatoid arthritis, etc.) play an important role in the treatment.

The biological clock is a complex multi-loop feedback regulation network. Agonists or inhibitors that act on the same target can be both beneficial and harmful. When evaluating the pharmacological effects of small molecule regulators of the biological clock, the continuous pharmacological effects of the compounds should be comprehensively investigated.

 

 

 

 

 


(source:internet, reference only)


Disclaimer of medicaltrend.org