TABLE 1.

Strategies to target Notch signaling.

Class	Agent(s)	Target	Mechanism	Cancer type; in vivo/in vitro model	Treatment-related toxicities	References
GSI	PF03084014, MK0752	γ-secretase complex	Juxtamembrane cleavage and NICD dissociation	T-ALL*, breast*, lung adenocarcinomas*, thyroid*, prostate*, CNS malignancies*	Gastrointestinal toxicities, diarrhea, nausea, rash, fatigue	(140), NCT00645333, NCT01098344
	A5226A	Nicastrin	Inhibition of γ-secretase activity	Lymphoblastic leukemiat, NSCLCt	na	(141)
Blocking peptides	SAHM1	MAML1	Direct binding to pre-assembled Notch1–CSL/RBP-Jκ complexes and competitive inhibition of the MAML1 co-activator binding	T-ALLt, murine asthma model	na	(142, 143)
Blocking antibodies	OMP-59R5, anti-NRR1, anti-NRR2	Notch1, Notch2, Notch3	Blocking receptor mediated signaling	Stage IV NSCLC*, extensive stage small-cell lung cancer*	Atrial fibrillation, diarrhea	PINNACLE (NCT01859741), (144, 145)
	OMP-21M18, REGN421	hDLL4	Humanized antibody that blocks DLL4 interactions with Notch	Breastt, colont, ovariant, pancreatict, NSCLCt & patients with advanced malignancies*	Hypertension, congestive heart failure	NCT01189968, NCT01189929, NCT00871559, (146, 147)
Decoys [soluble ligand or receptor forms]	N11–24	DLL1,4	Pan ligand blocking	Mammary, pancreatic, lung and melanoma tumor models	na	(28)
	N11–36	JAG1,2
	N11–13	DLL1,4	Specific blocking of Delta-like ligands
	N110–24	JAG1, 2	Specific blocking of Jagged ligands
	sJ1, sJ1N–E3	JAG1	Endogenous Jagged1	LLC		(6)
L-Fucose analogs	6-alkynyl and 6-alkenyl fucose	Notch ECD fucosylation	Substrate for POFUT-1 incorporated into Notch1 ECD, preventing binding to DLL1,4	T cell differentiation model [OP9 stromal coculture]	na	(98)
Soluble multivalent ligands	cDLL1	Notch1-4	Provides DLL1 stimulus to activate Notch receptors	Lung tumor models, in vitro mouse and human T cell cultures	na	(2, 5)

Examples of Notch-targeting agents used in in vitro, pre-clinical and clinical studies. *, tested in clinical trial; t, preclinical/in vitro data.