Tubastatin A

Tubastatin A is a potent and selective HDAC6 inhibitor with an IC₅₀ value of 15 nM ^[1]. Tubastatin A is also a novel GPX4 inhibitor that directly binds to GPX4 and induces ferroptosis in breast cancer cells^[2].

Tubastatin A protected against HCA induced neuronal cell death in a dose-dependent manner. Tubastatin A induced the hyperacetylation of α-tubulin at 2.5 μM^[1]. Tubastatin A (32.5µM, 30µM) can inhibit cell colony formation and migration ability and promote apoptosis^[3]. Tubastatin A can effectively upregulate the levels of SOD1 and HO-1 and reduce the oxidative stress of chondrocytes ^[4]. Tubastatin A at 10 μM also significantly inhibited cell proliferation in cholangiocarcinoma cells^[5].

Tubastatin A (50mg/kg/day) treatment effectively reduces the expression of HDAC6 in the cartilage of osteoarthritis mice and improves osteoarthritis in mice with surgically destroyed medial meniscus (DMM)^[4]. Tubastatin A treatment reduced tumor growth and induces ciliogenesis in rat orthotopic model of cholangiocarcinoma at 10 mg/kg^[5].

References:
[1] Butler KV, Kalin J, Brochier C, Vistoli G, Langley B, Kozikowski AP: Rational design and simple chemistry yield a superior, neuroprotective HDAC6 inhibitor, tubastatin A. J Am Chem Soc 2010, 132(31):10842-10846.
[2] Liu, Shan., Zhang, Hai-Liang., Li, Jing., Ye, Zhi-Peng., Du, Tian. Tubastatin A potently inhibits GPX4 activity to potentiate cancer radiotherapy through boosting ferroptosis. Redox biology, 2023.
[3] Urdiciain A, Erausquin E, Meléndez B, Rey JA, Idoate MA, Castresana JS. Tubastatin A, an inhibitor of HDAC6, enhances temozolomide-induced apoptosis and reverses the malignant phenotype of glioblastoma cells. Int J Oncol. 2019 May;54(5):1797-1808.
[4] Shen Z, Ji K, Cai Z, Huang C, He X, Xu H, Chen G. Inhibition of HDAC6 by Tubastatin A reduces chondrocyte oxidative stress in chondrocytes and ameliorates mouse osteoarthritis by activating autophagy. Aging (Albany NY). 2021 Mar 19;13(7):9820-9837.
[5] Gradilone SA, Radtke BN, Bogert PS, Huang BQ, Gajdos GB, LaRusso NF: HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer Res 2013, 73(7):2259-2270.