Table 2.

Representative synthetic and natural small molecules that influence circadian core clock in cancer.

Synthetic Anticancer Chronobiotics
(A) REV-ERBs; RORs; CRY1/2
Compound	Chemical Structure	Function	Mechanism	System	Reference
SR6542 (GSK4112)		REV-ERB agonist	Inhibition of Bmal1 expression	HepG2 liver cell line	[75]
GSK2945		REV-ERB agonist	1000-fold selectivity for REV-ERB versus LXRα	HepG2 liver cell line	[78]
SR9009		REV-ERB agonist	Circadian clock repressor Cytotoxic properties to a range of cancers e.g., brain, leukemia, breast, colon; in vivo inhibition of in vivo glioblastoma growth	Human gliobalstoma T98G cells; HepG2 cells	[73,79,80,81]
SR9011		REV-ERB agonist
SR1078		ROR agonist	Activation of target gene expression, such as G6Pase and fibroblast growth factor 21; inhibition of HepG2 and Hep3B hepatoma cell growth both in vitro and in vivo	HepG2 cells and mouse liver	[83]
ARN5187		REV-ERBα/β agonist REV-ERBα IC50: 790 nM REV-ERBβ IC50: 560 nM; Inhibitor of autophagy	Apoptotic induction/anticancer activity; blocking later stages of autophagy	Breast cancer BT-474 cells	[86]
MLN4924		RORα stabilization	Transactivation of Bmal1; induction of G2/M cell cycle arrest and apoptosis	U2OS osteosarcoma cells	[95]
KS15		CRY inhibitor	Activation and enhancement of CLOCK-BMAL1-evoked E-box mediated transcription	MCF-7 breast cancer cell line	[100,102,103]
(B) Casein Kinase
Longdaysin		CKIα/δ inhibitor IC50: CKIα 5.6 μM IC50: CKIδ 8.8 μM	The period-lengthening effect	Cells, tissues, and zebrafish in vivo	[108]
DK359 (caged longdaysin)		Inactive against CKIα/δ	Temporal control of the clock period	Cells, tissues, and zebrafish in vivo	[114]
CX-4945 (silmitasertib)		CK2 inhibitor IC50: CK2 1 nM	Broad antiproliferative activity; supression of angiogenesis; decreased phosphorylation of Akt substrate p21	Panel of cancer cell lines; human umbilical vein endothelial cell (HUVEC); murine xenograft models	[124]
GO289		CK2 inhibitor IC50: 7 nM	Inhibition of multiple phosphorylation sites on clock proteins	Human U2OS osteosarcoma cells	[125]
(C) Cyclin Dependent Kinase
LY2857785		CDK9 inhibitor IC50: 11 nM	Enhancement of REV-ERBα expression; liberation of REV-ERBα from CDK9; tuning RORE-mediated transcriptional activity	mPer2Luc mouse embryonic fibroblast (MEF) cell line	[130]