LMK235 | Selective HDAC4/5 inhibitor

LMK235 (1418033-25-6) is a potent and selective inhibitor of HDAC4 (IC₅₀ = 11.9 nM) and HDAC5 (IC₅₀ = 4.2 nM).¹ Cytotoxic against human ovarian cancer cell lines A2780 and A2780 CisR (IC₅₀’s = 0.49 µM and 0.32 µM respectively). It displayed synergistic effects with cisplatin and restored sensitivity in platinum-resistant cell lines.^1,2 LMK235 induced apoptosis in pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1³ and in multiple myeloma cells⁴. It also induced autophagy and cell death via SCNN1A downregulation in glioblastoma cells.⁵ LMK235 reduced hypertension in mouse and rat models via inhibition of vascular constriction and vessel hypertrophy.⁶ LMK235 significantly increased neurite outgrowth via increased BMP-Smad-dependent transcription in SH-SY5Y cells and exerted neuroprotective effects against neurodegeneration induced by MPP⁺ suggesting possible therapeutic potential in treating Parkinson’s disease.⁷

References/Citations:

1. Marek et al. (2013), Histone Deacetylase (HDAC) Inhibitors with a Novel Connecting Unit Linker Region Reveal a Selectivity Profile for HDAC4 and HDAC 5 with Improved Activity against Chemoresistant Cancer Cells; J. Med. Chem. 56 427
2. Moita et al. (2020), Priming with HDAC Inhibitors Sensitizes Ovarian Cancer Cells to Treatment with Cisplatin and HSP90 Inhibitors; Int. J. Mol. Sci. 21 8300
3. Wanek et al. (2018), Pharmacological Inhibition of Class IIA HDACs by LMK-235 in Pancreatic Neuroendocrine Tumor Cells; Int. J. Mol. Sci. 19 3128
4. Li et al. (2019), Histone deacetylase inhibitor LMK-235-mediated HO-1 expression induces apoptosis I multiple myeloma cells via JNK/AP-1 signaling pathway; Life Sci. 223 146
5. Chang et al. (2022), A Selective Histone deacetylase inhibitor LMK235 Induces Autophagy and Cell Death via SCNN1A Downregulation in Glioblastoma Cells; Cancers (Basel) 14 4537
6. Choi et al. (2019), Histone deacetylase inhibitor LMK235 attenuates vascular constriction and aortic remodeling in hypertension; J. Cell Mol. Med. 23 2801
7. Mazzocchi et al. (2021), LMK235, a small molecules inhibitor of HDAC4/5, protects dopaminergic neurons against neurotoxin- and α-synuclein-induced degeneration in cellular models of Parkinson’s disease; Mol. Cell Neurosci. 115 103642