SB939: A Potent and Orally Active HDAC Inhibitor for the Treatment of Hematological Malignancies.

Konference: 2007 49th ASH Annual Meeting - účast ČR

Kategorie: Maligní lymfomy a leukémie

Téma: Postery

Číslo abstraktu: 1603

Autoři: Sangthongpitag Kanda; Stunkel Walter; Zahid Q. Bonday; C. Goh Kee; Xukun Wang; Wu Xiaofeng; Hu Changyong; Haishan Wang; Yu Niefang; Sun Eric; Michael Entzeroth; Kantharaj Ethirajulu; Chien-Shing Chen; M. Jeanette Wood

Histone deacetylases (HDACs) are emerging new molecular targets for cancer therapy. Small-molecule HDAC inhibitors have been developed and shown to induce tumor cell cytostasis, differentiation and apoptosis in experimental models and efficacy in clinical trials in various hematological malignancies following intravenous and/or oral administration. SB939 is a novel HDAC inhibitor with improved metabolic, pharmacokinetic and pharmacological properties compared to other HDAC inhibitors currently in clinical trials1. The objective of this study was to characterize the anti-tumor efficacy of SB939 in preclinical models of hematological malignancies. SB939 selectively inhibits HDAC class I and II isozymes, with Ki values ranging from 16 to 247 nM. It inhibited the proliferation of cell lines from various haematological malignancies, including leukemia, lymphoma and multiple myeloma with IC50 values ranging from 80 nM to 200 nM. It induced cell cycle arrest leading to apoptotic cell death in tumor cell lines as well as primary cells isolated from patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML). SB939 has excellent pharmacokinetic properties and tolerability after oral administration in mice1. The oral anti-tumor efficacy of SB939 was evaluated in models of AML (MV4-11) and lymphoma (Ramos) with the tumors grown subcutaneously in nude mice. After daily oral treatment at 50mg/kg (21 days for MV4-11; 14 days for Ramos), SB939 significantly reduced tumor growth in both models (%TGI values were 116% and 100% respectively in MV4-11 and Ramos). In the MV4-11 model, SB939 induced complete tumor regression, in 6/10 mice. In conclusion, our data demonstrate that SB939 is a potent, orally active anti-tumor drug with potential for the treatment of various types of hematological malignancies.

1Kanda Sangthongpitag, Haishang Wang, Pauline Yeo, Liu Xin, Evelyn Goh, Lee Sun New, Peizi Zeng, Xiaofeng Wu, Changyong Hu, Tony Ng and Kantharaj Ethirajulu. ADME attributes of SB939, a best-in-class HDAC Inhibitor, and its PK/PD correlation in the Pharmacological Species. EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics Prague Congress Centre, 2006, Nov 7-10; Prague, Czech Republic, Abstract number 166

Abstract #1603 appears in Blood, Volume 110, issue 11, November 16, 2007

Keywords: Acute Myeloid Leukemia|Chronic Myeloid Leukemia|B-Cell Lymphoma

Disclosure: Employment: All authors except C.S. Chen are current or ex-employees of S*BIO Pte Ltd.

Ownership Interests: Some of the authors hold stock options issued by S*BIO Pte Ltd.

Saturday, December 8, 2007 5:30 PM

Session Info: Poster Session: Molecular Pharmacology: Novel Therapies (5:30 p.m.-7:30 p.m.)

Datum přednesení příspěvku: 8. 12. 2007