. Author manuscript; available in PMC: 2021 Oct 19.

Published in final edited form as: Nat Rev Drug Discov. 2021 Feb 15;20(4):287–307. doi: 10.1038/s41573-020-00109-w

Table 2 |.

Preclinical studies of small-molecule modulators targeting clock components and key regulators

chemical modulators	Mechanism of action	Physiological effects	Refs
*CRY1/CRY2*
KL001 and CRY-stabilizing derivative (SHP656, KL101 and TH301)	Stabilize CRY, lengthen period, reduce amplitude	Improvement of glucose tolerance in obese mice, inhibition of glioblastoma stem cell proliferation in vitro, inhibition of glioblastoma tumour growth in vivo, enhancers of brown adipocyte differentiation	^{94,194,196,197}
2-Ethoxypropanoic acid (KS15)	Inhibits CRY, activates E-box transcription, reduces amplitude	Inhibition of breast cancer cell growth	²³¹
*REV-ERBs*
GSK4112	Enhances REV-ERB and NCOR peptide interaction	Inhibition of gluconeogenesis and inflammatory response in primary cells	^129,179,189
SR9009, SR9011	Derived from GSK4112, they are selective agonists for REV-ERB that alter circadian behaviour, clock gene expression (BMAL1, PERI, and PER2) and expression of some glioblastoma stem cell markers (for example, OLIG2 and SOX2)	Improvement of glucose homeostasis in obese mice, promotion of wakefulness, anxiolytic, inhibition of glioblastoma stem cell proliferation	^94,181,183
SR8278	GSK4112-derived antagonist that increases expression of REV-ERB target genes (for example, BMAL1, PCK1 and G6PC1) in cells	Anxiety attenuation and amelioration of myocardial injury	^82,189
*RORs*
Nobiletin	Agonist, enhances amplitude and lengthens period	Metabolic homeostasis improvement in obese/diabetic mice; broad efficacies with regard to inflammation and atherosclerosis	^188,232,233
Neoruscogenin	Agonist promoting ROR interaction with NCOA2/TIF2, activates BMAL1 expression	Activation of hepatic expression of ROR metabolic target genes	²³⁴
SR1001	Derived from T0901317 with high inverse agonist activity and selectivity for RORα and RORγt	Inhibition of T_H17 cell differentiation and autoimmunity	¹⁹³
SR2211, SR1555, digoxin, ursolic acid, ML209	RORγ inverse agonist	Inhibition of T_H17 cell differentiation	^189,191,192
SR3335	RORα inverse agonist	Reduction of blood glucose level in obese mice	²³⁵
SR1078	RORα agonist	Induction of apoptosis and inhibition of hepatoma cell growth	²³⁶
*CK1 kinases*
CKI-7, IC261, D4476, PF-670462, PF-4800567 longdaysin, LH846, compounds 1–3 among others	Inhibitors, lengthen period	Pharmacological inhibition of CK1, significantly lengthen circadian rhythms mainly by nuclear retention of PER2. CK1 is broadly involved in various pathophysiologies, including familial sleep and mood disorders	^{199–201,237}
*ADORA2B*
BAY 60-6583	ADORA2B agonist, PER2 stabilization	Enhancement of adenosine signalling and cardioprotection against myocardial ischaemia	^74,238
*PER2*
Lithium	Increased transcription of PER2, lengthens period and enhances amplitude of PER2 rhythms	Treatment of bipolar disorder associated with circadian rhythm disruptions	²³⁹

For additional clock-modulating compounds, see REFS^{5,189,192,237}. ADORA2B, A_2B adenosine receptor; CK1, casein kinase 1; CRY, cryptochrome; NCOR, nuclear receptor co-repressor; PER2, period circadian protein homologue 2; ROR, RAR-related orphan receptor; T_H17 cell, interleukin-17-producing T helper cell.