HDAC2 Inhibitor

(S)-Trichostatin A ((S)-TSA) is a HDAC6-selective inhibitor with IC₅₀s of 9.88 nM and 11.1 nM for Zebrafish HDAC6 and Human HDAC6, respectively. (S)-Trichostatin A weakly inhibits other human HDACs.

HDAC-IN-72 (compound 7j) is the most potent HDAC1 (IC₅₀=0.65 μM), HDAC2 (IC₅₀=0.78 μM), HDAC3 (IC₅₀=1.70 μM) inhibitor and antiproliferative compound. HDAC-IN-72 can be used for breast cancer research.

HDAC2-IN-4 is a HDAC2 inhibitor with an IC₅₀ of 4.2 nM against human HDAC2. HDAC2-IN-4 binds to the active site of HDAC2 via hydrogen bonding and hydrophobic interactions, forming a thermodynamically stable and kinetically compatible protein-ligand complex to inhibit enzymatic activity. HDAC2-IN-4 inhibits cancer cell proliferation and exhibits low toxicity to normal cells. HDAC2-IN-4 can be used in studies related to human endocervical adenocarcinoma and Burkitt lymphoma.

HDAC-IN-56 ((S)-17b) is an orally active class I histone deacetylase (HDAC) inhibitor with IC₅₀ values of 56.0 ± 6.0, 90.0 ± 5.9, 422.2 ± 105.1, >10000 nM for HDAC1, HDAC2, HDAC3, and HDAC4-11, respectively. HDAC-IN-56 has potent inhibitory activity while strongly increasing intracellular levels of acetylhistone H3 and P21 and effectively inducing G1 cell cycle arrest and apoptosis.HDAC-IN-56 has antitumor activity .

HDAC-IN-79 (compound 4) is an orally active dual xanthine oxidase-HDAC inhibitor (Xanthine oxidase: IC₅₀=6.6 nM; HDAC1: IC₅₀=134 nM; HDAC2: IC₅₀=284 nM; HDAC3: IC₅₀=173 nM; HDAC6: IC₅₀=1.32 nM;), with significant in vivo anti-hyperuricemia and anti-tumor activities. HDAC-IN-79 is the most potent cell growth inhibitor (IC₅₀=0.706 μM) of leukemia HL60 cells, induces apoptosis and autophagy, and can regulate the expression levels of signature biomarkers associated with intracellular HDAC inhibition.

HDAC-IN-96 (Compound 3f) is a selective HDAC1/2 inhibitor with IC₅₀ values of 457.1 and 433.7 nM. HDAC-IN-96 has strong inhibitory activity against multiple hematological tumor cells (RS4;11, K562, RPMI-8226, U266), with IC₅₀ values ranging from 2.11 to 5.35 μM. HDAC-IN-96 can induce cancer cells apoptosis and S phase arrest. HDAC-IN-96 can be used for the research of cancer, such as acute lymphoblastic leukemia.

Aurora kinase/HDAC-IN-1 is an orally active dual Aurora kinase and HDAC inhibitor that inhibits Aurora A (IC₅₀ = 116 nM), Aurora B (IC₅₀ = 225 nM), HDAC1 (IC₅₀ = 164 nM), and HDAC2 (IC₅₀ = 346 nM).Aurora kinase/HDAC-IN-1 promotes histone H3 acetylation, inhibits Aurora A phosphorylation and downstream signaling, and induces apoptosis via G2/M cell-cycle arrest. Aurora kinase/HDAC-IN-1 exhibits potent antiproliferative activity in colorectal cancer cells, with an IC₅₀ value of 30.2 nM in HCT-116 cells.Aurora kinase/HDAC-IN-1 significantly suppresses tumor growth in an HCT-116 colorectal cancer xenograft mouse model.

LSD1/HDAC-IN-3 is a inhibitor targeting class I HDAC and LSD1 enzymes. LSD1/HDAC-IN-3 inhibits HDAC1, HDAC2, HDAC3, and LSD1 with IC₅₀ values of 1702 nM, 842 nM, 358 nM, and 1074 nM, respectively. LSD1/HDAC-IN-3 exhibits antioxidant effects in H2O2-stressed ARPE-19 and 661W retinal cells, increasing levels of acetylated and methylated histone H3. LSD1/HDAC-IN-3 enhances photoreceptor survival in the rd10 mouse model of retinitis pigmentosa. LSD1/HDAC-IN-3 can be used for the study of inherited retinal diseases such as retinitis pigmentosa (RP).

HDAC1-IN-6 (compound 1) is an inhibitor of HDAC1 and 11, with an IC₅₀ of 1.9 μM and 1.6 μM, respectively. HDAC1-IN-6 induces differentiation in AML cells.

Tubulin/HDAC-IN-4 (compound 9n) is a dual Tubulin and HDAC inhibitor with IC₅₀ values of 0.73, 0.43, 0.62, 2.34 µM for HDAC1, HDAC2, HDAC6, HDAC7, respectively. Tubulin/HDAC-IN-4 inhibits the tubulin polymerization by targeting the colchicine binding site. Tubulin/HDAC-IN-4 induces apoptosis and cell cycle arrest at G2/M phase. Tubulin/HDAC-IN-4 induces a significant elevation of intracellular ROS levels. Tubulin/HDAC-IN-4 shows anti-angiogenesis activity and anticancer activity.

HDAC6-IN-79 is a HDAC6 inhibitor with an IC₅₀ of 98.40 nM, and it also exhibits inhibitory activity against other HDAC subtypes (HDAC1: 639.0 nM, HDAC2: 798.9 nM, HDAC8: 865.7 nM, HDAC4: 1187 nM). HDAC6-IN-79 induces acetylation of α-tubulin and histone H3, reduces the viability of cancer cells, activates the autophagy pathway and induces apoptosis. HDAC6-IN-79 can be used for research related to urothelial carcinoma (bladder cancer).

TH-6 is a potent HDAC inhibitor with IC₅₀s of 0.115, 0.135, 0.242, 0.138, 2.120 µM for HDAC1, HDAC2, HDAC3, HDAC6, HDAC8, respectively. TH-6 inhibits cell migration and invasion. TH-6 induces apoptosis and cell cycle arrest at G2/M phase. TH-6 shows anti-tumor activity.

HDAC-IN-45 (Compound 14) is a small molecule HDAC inhibitor and has anticancer activity, also can forms a hydrogen bond with residue Y303. HDAC-IN-45 (Compound 14) has substantial inhibitory effects towards HDAC1, 2 and 3 isoforms with IC₅₀ values of 0.108, 0.585 and 0.563 μM respectively.

ROCK/HDAC-IN-1 (Compound 10h) is an orally active ROCK/HDAC inhibitor. ROCK/HDAC-IN-1 inhibits ROCK1/2 (IC₅₀: 254.9 nM, 58.18 nM) and HDAC1/2/3/6/8 (IC₅₀: 9.09, 8.03, 6.26, 0.41, 7.69 nM). ROCK/HDAC-IN-1 stimulates the activation of DAMPs, specifically Calreticulin (CRT) exposure and HMGB1 release, indicating that it is a potential ICD inducer.. ROCK/HDAC-IN-1 has antiproliferative activity against breast cancer cells (IC₅₀: 0.37 μM for MDA-MB-231 cell), and inhibits tumor growth and activates T cells without apparent toxicity.

HDAC2-IN-1 (Compound 17) is a brain penetrant, orally active, competitive HDAC2 inhibitor with an IC₅₀ of 0.5 μM. HDAC2-IN-1 also inhibits HDAC1 and HDAC8 with IC₅₀s of 1.61 μM and 0.98 μM, respectively.

HDAC-IN-36 (compound 23 g) is an orally active and potent HDAC (histone deacetylase) inhibitor, with an IC₅₀ of 11.68 nM (HDAC6). HDAC-IN-36 promotes apoptosis, autophagy and suppresses migration. HDAC-IN-36 shows anti-tumor and anti-metastatic activity, and can be used for breast cancer research.

HDAC-IN-39 (compound 16c) is a potent HDAC inhibitor, with IC₅₀ values of 1.07 μM (HDAC1), 1.47 μM (HDAC2), and 2.27 μM (HDAC3), respectively. HDAC-IN-39 also significantly inhibits microtubule polymerization. HDAC-IN-39 induces cell cycle arrest at the G2/M phase. HDAC-IN-39 displays promising anticancer activity against resistant cancer cells.

NMDAR/HDAC-IN-1 (Compound 9d) is a dual NMDAR and HDAC inhibitor with a K_i of 0.59 μM for NMDAR and IC₅₀ values of 2.67, 8.00, 2.21, 0.18 and 0.62 μM for HDAC1, HDAC2, HDAC3, HDAC6 and HDAC8, respectively. NMDAR/HDAC-IN-1 efficiently penetrates the blood brain barrier.

DS-103 is an inhibitor for HDAC that inhibits HDAC1, HDAC2, HDAC3, HDAC6 and HDAC8 with IC₅₀s of 0.029, 0.123, 0.022, 0.367 and 9.26 μM, respectively. DS-103 inhibits Plasmodium falciparum 3D7 with IC₅₀ of 5.08 μM. DS-103 exhibits cytotoxicity in cells A2780 and Cal27 with IC₅₀ of 1.48 μM and 1.47 μM, reverses Cisplatin (HY-17394) resistance in A2780 and Cal27 with IC₅₀ of 4.62 μM and 2.23 μM. DS-103 exhibits synergistic effect with Cisplatin (HY-17394), enhances Cisplatin-induced apoptosis.

TNI-97 is a selective and orally active HDAC6 inhibitor, with an IC₅₀ of 0.2 nM. TNI-97 potently inhibited TNBC cell MDA-MB-453 growth and clonogenicity. TNI-97 induces PANoptosis including apoptosis, necroptosis and pyroptosis in MDA-MB-453 cells. TNI-97 shows antitumor activity in the mice carrying the MDA-MB-453 xenograft or carrying murine-derived TNBC cell allografts. TNI-97 can be used for the study of triple-negative breast cancer.