MS-275

by Selleckchem | Mar 19 2012

Introduction: HDAC inhibition

In most cancerous tissue there exists an imbalance between regulatory pathways that came be exploited for chemotherapeutic activity. One of the pathways that exhibits such activity is the acetylation / de-acetylation pathway [1]. The regulatory enzyme in this pathway is referred to as Histone deacetylase (HDAC) and it operates in balance with Histone acetyl transferase. The addition or removal of an acetyl group causes the protein conformational shape to change and this in turn triggers either an attraction or inhibition of a protein complex formation [2;3]. This action sends a signal to the nucleus to being or stop growth actions. There are many HDAC enzymes located in the cellular cytosole or within the nucleus membrane and most activity is controlled by a zinc catalyst, one small group requires NAD+ to function instead.

MS275 is a small molecule under development at the phase I stage for the treatment of leukemia’s and solid tumors [4-7] Note is made of the fact that a analogue of MS275 with a 3` aminophenyl substitution instead of the 2`aminophenyl substitution did not have any activity towards HDAC indicating that the 2`aminophenyl position is essentially for the HDAC inhibitory role of this molecule [8;9]. Preclinical and clinical testing has demonstrated significant advantages to this potential chemotherapeutic agent.

MS275: Properties and Availability

Syndax Developments is a company that markets the new molecule called the MS275 inhibitor. Like most HDAC inhibitors the MS275 structure is based on a benzamide central core with its activity modulated by the substituted side chains. Activity for this compound was determined in a series of kinases and MS275 IC50 indicated that it was targeted to HDAC 1, 2 &3 with a similar concentration (±2µM). Buffer preparation for this compound is difficult since MS275 solubility in various solvents is extremely poor (maximal aqueous concentration 16 µg/ml). For general purposes this compound is soluble in DMSO (max 25 mg/ml), although it must be noted that a slight warming of the solution is necessary for complete dissolution. It must also be noted that MS275 is listed a significant teratogen and embryo-toxic, caution in handling is advised. MS275 stability in it solid state is listed as being fair, with recommendation to store at -20°C for no longer than 2 years. A separate specification is made stating that this compound is light sensitive. The MS275 price of a 10 mg vial can range from $69 up to $720 from a variety of MS275 suppliers. Researchers can buy MS275 without restriction but cost is dependent on the supplier.

MS275: Preclinical investigations

Subsequent to being shown to inhibit purified HDAC and over expression of histones in various tumor cells lines, MS275 was tested against a murine model of tumor xenografts and shown to induce p21, decrease S-phase cells while increasing G1 phase in the cell cycle distribution resulting in significant anti-tumor activity[8] In human breast cancer cells MS275 was observed to induce the TGFßII protein but not the TGF-ß with significant anti-tumor response seen [10]. In a separate study MS275 was used in a panel of pediatric tumors covering a wide range of tumor types such as Ewing's sarcoma (EWS),osteosarcoma, rhabdomyosarcoma, retinoblastoma, medulloblastoma, rhabdoid tumors, neuroblastoma, and malignant undifferentiated sarcoma [11] A panel of prostate carcinoma xenografts was used to assess the effect of MS275 on radiosensitivity, After two courses of MS275 histone hyper-acceleration was observed making the cell more sensitive to radiation. These results plus more indicated that MS275 should be move to phase I clinical testing .

MS-275: Clinical Status

MS-275 clinical trials are being conducted at a phase I/II level for this molecule. Four preliminary reports have been issued with respect to refractory and acute leukemia, advanced solid tumors and solid tumors [4-7]. The MS275 HDAC inhibitor is currently under investigation in NSCLC, CML or AML (in combination with Azacitidine), in Refractory Myleod malignancies, AML and ALL (in combination with GM-CSF), advance solid tumors, metastatic melanoma, hematological cancer and Hepatocarcinoma.

References

1. Martin M, Kettmann R et al. Class IIa histone deacetylases: regulating the regulators. Oncogene 2007; 26(37):5450-5467.

2. Codd R, Braich N et al. Zn(II)-dependent histone deacetylase inhibitors: suberoylanilide hydroxamic acid and trichostatin A. Int J Biochem Cell Biol 2009; 41(4):736-739.

3. Rajendran P, Williams DE et al. Metabolism as a key to histone deacetylase inhibition. Crit Rev Biochem Mol Biol 2011; 46(3):181-199.

4. Gojo I, Jiemjit A et al. Phase 1 and pharmacologic study of MS-275, a histone deacetylase inhibitor, in adults with refractory and relapsed acute leukemias. Blood 2007; 109(7):2781-2790.

5. Ryan QC, Headlee D et al. Phase I and pharmacokinetic study of MS-275, a histone deacetylase inhibitor, in patients with advanced and refractory solid tumors or lymphoma. J Clin Oncol 2005; 23(17):3912-3922.

6. Pili R, Salumbides B et al. Phase I study of the histone deacetylase inhibitor entinostat in combination with 13-cis retinoic acid in patients with solid tumours. Br J Cancer 2012; 106(1):77-84.

7. Kummar S, Gutierrez M et al. Phase I trial of MS-275, a histone deacetylase inhibitor, administered weekly in refractory solid tumors and lymphoid malignancies. Clin Cancer Res 2007; 13(18 Pt 1):5411-5417.

8. Saito A, Yamashita T et al. A synthetic inhibitor of histone deacetylase, MS-27-275, with marked in vivo antitumor activity against human tumors. Proc Natl Acad Sci U S A 1999; 96(8):4592-4597.

9. Suzuki T, Ando T et al. Synthesis and histone deacetylase inhibitory activity of new benzamide derivatives. J Med Chem 1999; 42(15):3001-3003.

10. Lee BI, Park SH et al. MS-275, a histone deacetylase inhibitor, selectively induces transforming growth factor beta type II receptor expression in human breast cancer cells. Cancer Res 2001; 61(3):931-934.

11. Jaboin J, Wild J et al. MS-27-275, an inhibitor of histone deacetylase, has marked in vitro and in vivo antitumor activity against pediatric solid tumors. Cancer Res 2002; 62(21):6108-6115.