TMP195 is a selective class IIa histone deacetylase (HDAC) inhibitor with IC50 values of 0.111, 0.106, 47.8, 0.046, 11.7, and 0.009µM for HDAC4, 5, 6, 7, 8, and 9, respectively[1]. TMP195 binds to the drug-binding pockets of drug transporters ABCB1 and ABCG2, stimulating ATPase activity and weakening the drug efflux function of ABCB1 and ABCG2, thereby reversing the multidrug resistance mediated by ABCB1 and ABCG2[2]. TMP195 has been widely used to inhibit the growth of transplanted tumors and to develop combined therapies for effectively killing tumors[3].
In vitro, TMP195 treatment (25µM) for 48 hours significantly induced apoptosis and cell cycle arrest in H460 and H1703 cells, and led to mitochondrial dysfunction[4].
In vivo, TMP195 treatment significantly suppressed the growth of tumors in the MC38 xenograft mouse model by intraperitoneal injection at a dosage of 50mg/kg/day for 15 days and promoted the secretion of M1-type macrophage-related cytokines[5]. A single intraperitoneal injection of 50mg/kg TMP195 for 24 hours improved renal dysfunction in a mouse model of acute kidney injury (AKI) induced by lipopolysaccharide (LPS), reduced macrophage infiltration, and decreased the expression of cytokines and chemokines[6]. Daily intraperitoneal injection of TMP195 (50mg/kg) reduced the tumor burden and decreased lung metastasis in MMTV-PyMT tumor-bearing mice over a period of 13 days[7].
References:
[1] Lobera M, Madauss K P, Pohlhaus D T, et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group[J]. Nature chemical biology, 2013, 9(5): 319-325.
[2] Wu C P, Lusvarghi S, Wang J C, et al. The selective class IIa histone deacetylase inhibitor TMP195 resensitizes ABCB1-and ABCG2-overexpressing multidrug-resistant cancer cells to cytotoxic anticancer drugs[J]. International journal of molecular sciences, 2019, 21(1): 238.
[3] Cassetta L, Pollard J W. Repolarizing macrophages improves breast cancer therapy[J]. Cell research, 2017, 27(8): 963-964.
[4] Park J, Chen Y Y, Cao J J, et al. MYC plus class IIa HDAC inhibition drives mitochondrial dysfunction in non-small cell lung cancer[J]. Cell Reports, 2025, 44(6).
[5] Han Y, Sun J, Yang Y, et al. TMP195 exerts antitumor effects on colorectal cancer by promoting M1 macrophages polarization[J]. International journal of biological sciences, 2022, 18(15): 5653.
[6] Zhang W, Guan Y, Bayliss G, et al. Class IIa HDAC inhibitor TMP195 alleviates lipopolysaccharide-induced acute kidney injury[J]. American Journal of Physiology-Renal Physiology, 2020, 319(6): F1015-F1026.
[7] Guerriero J L, Sotayo A, Ponichtera H E, et al. Class IIa HDAC inhibition reduces breast tumours and metastases through anti-tumour macrophages[J]. Nature, 2017, 543(7645): 428-432.