Epigenetic Therapy as a Putative Molecular Target to Modulate B Cell Biology and Behavior in the Context of Immunological Disorders

Table 1

Main iHDACs used for preclinical and translational studies. The table provides information regarding the name of the iHDAC, the IC₅₀, and registered trials found at clinicaltrials.gov in addition to published papers that have used iHDACs to better understand the relevance of HDAC activity in the context of B cell behavior and biology. Chemical structures were obtained from PubChem (https://pubchem.ncbi.nlm.nih.gov/).

iHDAC	IC50	Clinical trial identifier	HDAC specificity	Chemical structure	Biologic event	Cell type	Model	Reference
Citarinostat (ACY-241)	2.6 nM (HDAC 6) and 46 nM (HDAC 3)	No trials registered	HDACs 1, 2, 3, and 6		Inhibition of plasma cell myeloma proliferation and survival; cell cycle disruption	MM1, H929, U266	Human	[74]
ACY-738	1.7 nM for HDAC 6 selectively	No trials registered	HDACs 1, 2, 3, and 6		Pre-B cell growth inhibition in lupus disease	MRL/lpr bone marrow cells	Mouse	[68]
BML-281	0.002 nM (HDAC 6), 271 nM (HDAC 1), 252 nM (HDAC 2), 0.42 nM (HDAC 3), 6851 nM (HDAC 8), 90.7 nM (HDAC 10)	No trials registered	HDAC 6		Blocks B cell infiltration in acute colitis	CD19^+ B lymphocyte	Mouse	[71]
Dacinostat (LAQ824)	32 nM	No trials registered	Pan iHDAC		Decreases viability in B-ALL, multiple myeloma, and B lymphoma cells	SEMK; RS4;11; SEMK2; 697; Namalwa; Daudi; Ramos; MM1S-N; OPM2; PMI8226	Human	[75]
Givinostat (ITF2357)	BCR-ABL signaling pathway	No trials registered	Classes I, II		Cell proliferation inhibition and apoptosis induction in chronic myelogenous leukemia, BCR-ABL1-positive and childhood B acute lymphoblastic leukemia	K-562, SUP-B15	Human	[76]
LMK-235	11.9 nM (HDAC 4), 4.2 nM (HDAC 5)	No trials registered	HDACs 4, 5		Induces apoptosis and BCLA1 overexpression in diffuse large B cell lymphoma	OCI-Ly10, OCI-Ly3	Human	[77]
Entinostat (MS-275)	0.51 μM (HDAC 1), 1.7 μM (HDAC 3) in cell-free assays	(1) NCT03925428; (2) NCT00098891; (3) NCT00020579	HDACs 1, 3, 4, 6, 8, and 10		Proliferation inhibition and apoptosis induction; enhancement of DNA damage response in plasma cell myeloma	U266, MM1.R, RPMI8226	Human	[78]
					Dose-/time-dependent cell death, gene expression disruption, and CD20 upregulation in rituximab-sensitive Burkitt lymphoma (BL) and RL (germinal centre B cell)	Raji-4RH, RL-4RH, and U2932-4RH and lymphoma cells derived from patients with untreated or relapsed/refractory B cell lymphoma	Human	[79]
					Decreases cell viability in B-ALL, B-lymphoma, and multiple myeloma cell lines	SEMK2, RS4;11, SEMK2, 697, Namalwa, Daudi, Ramos, MM1S-LN, OPM2, RPMI8226	Human	[75]
Panobinostat (LBH589)	5 nM in a cell-freeassay	(1) NCT01282476; (2) NCT01238692; (3) NCT01523834; (4) NCT00978432; (5) NCT00918333; (6) NCT01261247; (7) NCT00962507; (8) NCT02961816; European Medicines Agency approved for use and FDA accelerated approval for use in multiple myeloma (2015)	Classes I, II, and IV		Reduced cell number and viability; delayed division progression; decreases the number of CD138^+ antibody-secreting cells	B cell B220^+, CD19^+, IgM^+, IgD^+	Mouse	[69]
					Reduces autoantibody-producing plasma cells	MRL/lpr mouse autoimmunity	Mouse	[69]
					Primary germinal centre response inhibition	C57BL/6	Mouse	[69]
					Dose-dependent proliferation and tumor growth inhibition; apoptosis induction	CLBL-1 cells	Dog	[80]
RGFP966	0.08 μM in cell-free assay	No trials registered	HDAC 3		Induces apoptosis, decreases Bcl-2 and Bcl-xL expression.; Myc-mediated miR expression	Epstein-Barr virus-related Burkitt lymphoma	Human	[81]
						Eμ-myc; EM330	Mouse
Ricolinostat (ACY-1215)	5 nM in a cell-free assay. Low activity against HDAC 4/5/7/9/11, sirtuin 1, and sirtuin 2	(1) NCT02091063; (2) NCT02787369	HDAC 6		CD20 expression	Peripheral mononuclear cell from CLL patients; Raji cells	Human	[82]
Romidepsin (FK228, depsipeptide)	36 nM (HDAC 1), 47 nM (HDAC 2) in cell-free assays	(1) NCT01846390; (2) NCT02281279; (3) NCT00079443; (4) NCT00963274; (5) NCT01897012; (6) NCT02181218; (7) NCT00383565; (8) NCT03432741; (9) NCT01947140; (10) NCT01998035; FDA approved for cutaneous T cell lymphoma (2009)	HDACs 1, 2		Reduced cell number and viability	B cell B220^+, CD19^+, IgM^+, IgD^+	Mouse	[69]
Tacedinaline (CI994)	0.9 μM (HDAC 1), 0.9 μM (HDAC 2), 1.2 μM (HDAC 3), >20 μM (HDAC 8)	No trials registered	Class I		Dose-dependent proliferation inhibition	CLBL-1 cells	Dog	[80]
Trichostatin A (TSA)	1.8 nM in cell-free assays	No trials registered	Pan iHDAC		CD20 expression	Raji cells	Human	[82]
					Dose-dependent proliferation inhibition	CLBL-1 cells	Dog	[80]
Tubacin	4 nM in a cell-free assay	No trials registered	HDAC 6		CD20 expression	EBV-positive Burkitt lymphoma; EBV-negative Burkitt lymphoma; EBV-negative DLBCL cell lines; EBV-transformed lymphoblastoid cell lines; Peripheral mononuclear cell from CLL patients; Raji cells	Human	[82]
					Dose-dependent proliferation inhibition	CLBL-1 cells	Dog	[80]
Tubastatin A	15 nM in a cell-free assay	No trials registered	HDAC 6		CD20 expression	Raji cells	Human	[82]
Vorinostat (SAHA, MK0683)	10 nM in a cell-free assay	(1) NCT00097929; (2) NCT00764517; (3) NCT02589145; (4) NCT03150329; (5) NCT00667615; (6) NCT00703664; (7) NCT01193842; (8) NCT00972478; (9) NCT00875056; (10) NCT01567709; (11) NCT01120834; (12) NCT01276717; (13) NCT00992446; (14) NCT00499811; (15) NCT01116154; (16) NCT01789255; (17) NCT01500538; (18) NCT00601718; (19) NCT00275080; (20) NCT03259503; (21) NCT00253630; (22) NCT03842696; (23) NCT00791011; (24) NCT00994500; (25) NCT00217412; (26) NCT00837174; (27) NCT00720876; (28) NCT00005634; (29) NCT00918723; FDA approved for cutaneous T lymphoma (2006)	Classes I, II, and IV		CD20 expression	Raji cells	Human	[82]
					Reduced cell number and viability; delayed division progression; decreases the number of CD138^+ antibody-secreting cells	B cell B220^+, CD19^+, IgM^+, IgD^+	Mouse	[69]
					Dose-dependent proliferation inhibition	CLBL-1 cells	Dog	[80]
					Cell viability decrease, apoptosis induction	Raji, Raji-4RH, RL-4RH, RL, and patient primary tumors	Human	[83]
					Enhances apoptosis mediated by kinase inhibitors that affect BCR signaling and gene expression disruption in mantle cell lymphoma	Jeko-1, Mino	Human	[84]
					Induces cell death in rituximab-sensitive Burkitt lymphoma (BL) and RL (germinal centre B cell)	Lymphoma cells derived from patients with untreated or relapsed/refractory B cell lymphoma	Human	[79]
Scriptaid	9 μM (Ishikawa endometrial cancer cell line) and 55 μM (SK-OV-3 ovarian cancer cell line)	No trials registered	Pan iHDAC		CD20 expression	Raji cells	Human	[82]
					Dose-dependent proliferation inhibition	CLBL-1 cells	Dog	[80]
Suberohydroxamic acid (SBHA)	0.25 μM (HDAC 1), 0.3 μM (HDAC 3)	No trials registered	HDACs 1 and 3		Dose-dependent proliferation inhibition	CLBL-1 cells	Dog	[80]
					Src tyrosine kinase Gardner-Rasheed feline sarcoma viral (v-FGR) oncogene homolog (FGR) mediates SAHA resistance	BL-2, BL-41, BL-70, Blue-1, CA-46, Daudi, DG-75, DND-39, Namalwa, Raji (Burkitt lymphoma), Carnaval, Granta-452, HBL-1, HT, Kis-1, OCI-Ly1, OCI-Ly2, OCI-Ly3, OCI-Ly7, OCI-Ly10, SU-DHL-4, SU-DHL-6, TMD8, U2932, WSU-DLCL2, WSU-FSCCL (diffuse large B cell lymphoma)	Human	[85]
Valproic acid	Selectively induces proteasomal degradation of HDAC 2	(1) NCT01622439; (2) NCT00109824; (3) NCT02144623; Approved for use in the treatment of epilepsy	Pan iHDAC		Class-switch DNA recombination (CSR) and plasma cell differentiation	C57BL/6J	Mouse	[86, 87]
					CD20 expression	CLL cell line; CLL patients	Human	[88]
WT161	8.35 nM (HDAC 1), 15.4 nM (HDAC 2), 0.4 nM (HADC6)	No trials registered	HDACs 1, 2, and 6		Decreases cell viability in B-ALL, B lymphoma, and multiple myeloma cell lines	SEMK2, RS4;11, SEMK2, 697	Human	[75]