RRC ID |
41383
|
著者 |
Komatsu Y, Tomizaki KY, Tsukamoto M, Kato T, Nishino N, Sato S, Yamori T, Tsuruo T, Furumai R, Yoshida M, Horinouchi S, Hayashi H.
|
タイトル |
Cyclic hydroxamic-acid-containing peptide 31, a potent synthetic histone deacetylase inhibitor with antitumor activity.
|
ジャーナル |
Cancer Res
|
Abstract |
Cyclic hydroxamic-acid-containing peptide 1 (CHAP1), designed as a hybrid of trichostatin A and trapoxin, is a lead compound for the development of potent inhibitors of histone deacetylase (HDAC). In this study, we synthesized a series of CHAP derivatives and evaluated their biological activities by monitoring the potency of their inhibition of HDAC activity, their ability to augment the expression of MHC class-I molecules in B16/BL6 cells, and their effect on cell proliferation. A structure-activity relationship study using these three assay systems revealed several requirements of their structure for the strong inhibition of HDAC not only in the cell-free situation, but also in cells. When the structures of CHAP derivatives are represented as cyclo(-Asu(NHOH)-AA(2)-AA(3)-Pro or Pip-)(n), where Asu(NHOH) and Pip are zeta-hydroxamide-alpha-aminosuberic acid and pipecolic acid, respectively, (a) the tetrapeptide structure (n = 1) was better than the octapeptide one (n = 2); (b) AA(2) and AA(3) should be hydrophobic; and (c) the combination of amino acid chirality should be LDLD for the strongest inhibition of HDAC in cells (LDLD > LLLD, LDLL > LLDL). cyclo(-L-Asu(NHOH)-D-Tyr(Me)-L-Ile-D-Pro-) or CHAP31 was selected as one of the strongest CHAPs, and its biological activity was characterized further. CHAP31 was much more stable in the presence of cultured cells (t(1/2) > 3000 h) than trichostatin A (t(1/2) = 14.7 h) or trapoxin A (t(1/2) = 2.10 h). CHAP31 exhibited antitumor activity in C57BL x DBA/2 F(1) (BD2F(1)) mice bearing B16/BL6 tumor cells. Furthermore, CHAP31 inhibited the growth in four of five human tumor lines implanted into nude mice. These results suggest CHAP31 to be promising as a novel therapeutic agent for cancer treatment.
|
巻・号 |
61(11)
|
ページ |
4459-66
|
公開日 |
2001-6-1
|
PMID |
11389076
|
MeSH |
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Histone Deacetylase Inhibitors*
Humans
Hydroxamic Acids / chemistry
Melanoma, Experimental / drug therapy
Melanoma, Experimental / enzymology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Nude
Peptides, Cyclic / chemistry
Peptides, Cyclic / pharmacology*
Proline / chemistry
Stereoisomerism
Structure-Activity Relationship
Tumor Cells, Cultured
Xenograft Model Antitumor Assays
|
IF |
9.727
|
引用数 |
165
|
WOS 分野
|
ONCOLOGY
|
リソース情報 |
ヒト・動物細胞 |
SP2/0-Ag14(RCB0209) |