The S100 Protein Family as Players and Therapeutic Targets in Pulmonary Diseases

Table 2

Current drug development targeting S100 proteins.

Therapeutic approach	Agent	Possible S100 protein interaction	Current status	Study
Small molecule inhibition of S100 proteins; Quinoline-3-carboxamide derivatives	Tasquinimod (ABR-215050)	Oral administration that blocks S100A8 and S100A9 interacting with RAGE and TLR4	Phase II randomized, double-blind, placebo-controlled studies in men with minimally symptomatic metastatic CRPC	[168–170]
	Paquinimod (ABR-215757)	Oral administration that blocks S100A8/S100A9 interacting with TLR4	Phase I study demonstrated good tolerance in SLE patients, while a phase II study data never published	[176, 177]
	Laquinimod (ABR-215062)	Oral administration that blocks S100A8 and S100A9 interacting with RAGE and TLR4	Conflicting data in several multicenter phase II and III clinical trials in multiple sclerosis populations	[167, 172, 173]
Inhibitors of S100 proteins	Cromolyn (cromoglicic acid)	An antihistaminic drug binds to S100A1, S10012, S100A13, and S100P and disrupts interactions with RAGE	FDA approved 20 years ago as an antihistaminic drug, as a nasal spray (NasalCrom)	[178]
	Amlexanox	Interacts with S100A1, S100A4, and S100A13 to prevent their signaling	Used to treat recurrent aphthous ulcers but discontinued in the USA; In Japan, it is used to treat bronchial asthma, allergic rhinitis, and conjunctivitis	[184]; [228]
	Phenothiazines, such as trifluoperazine	Disrupt the interaction of S100A4 with myosin-IIA	Used to treat psychotic disorders, anxiety, nausea, and vomiting caused by chemotherapy	[229]
Indirect inhibitors of S100 protein signaling	Pentamidine	Downregulates inflammation mediated S100B	An antimicrobial agent to treat African trypanosomiasis, leishmaniasis, Balamuthia infections, babesiosis, and Pneumocystis pneumonia	[192]
	Arundic acid	Reduces S100B levels	A multicenter, dose-escalating, randomized, double-blind phase I trial was performed in acute ischemic stroke	[194, 230]
	Calcimycin (A23187)	Inhibit S100A4 expression	A calcium ionophore used against gram-positive bacteria and fungi. Also, in in vitro fertilization and to make artificial liposomes for cancer drugs	[185]
	Niclosamide (niclocide)	Inhibit S100A4 expression	Oral administered antihelminth drug	[231]
	Sulindac	Inhibit S100A4 expression	A nonsteroidal anti-inflammatory drug	[186]
Gene delivery approaches	Adenoviral-associated vector S100A1 gene delivery	Restored S100A1 levels to restore cardiomyocytes physiologic contractility, cardiac performance, and left ventricular remodeling	Only tested in animal models	[201, 202]
S100 neutralizing antibodies	Anti-S100A4, anti-S100P, anti-S100A9	Prevent extracellular signaling of S100 proteins	Only tested in animal models	[39, 195, 196]
S100 neutralizing peptides	Peptide-Fc fusion proteins (peptibody)	Depletes myeloid-derived suppressor cells getting to tumor and releasing S100 proteins	Only tested in animal models but reduced tumor growth	[197, 199]
Vaccines targeting S100 proteins	Anti-S100A9 vaccine	Prevent S100A9/CD36 signaling in a mouse ischemic stroke model	Only tested in animal models	[200]