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Discovery of 7-(4-(3-Ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyhep-tanamide(CUDC-101) as a Potent Multi-Acting HDAC, EGFR, and HER2 Inhibitor for the Treatment of Cancer
2015.03.06
Kiseon Baek
Contents Vorinostat, Erlotinib, Lapatinib
Introduction
Compound Design
Chemistry (Synthesis)
Result&Discussion
Non-hydroxamate type HDAC Inhibitor Enzyme assay
Hydroxamate type HDAC Inhibitor
SAHA(Vorinostat)
O
HN
O
NH
OH
화학명 N-hydroxy-N'-phenyl-octanediamide
분류 항악성종양제
적응증두 가지의 전신요법을 사용중이거나 사용한 후 , 진행성이거나 지속성 또는 재발성인 피부 T 세포 림프종
부작용 설사 , 구역 , 식욕부진 , 폐색전증 , 빈혈 등
상품명 Zolinza
개발회사 Merck
Erlotinib
화학명 N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine
분류 항악성종양제
적응증 비소세포폐암 , 췌장암
부작용 폐독성 , 심근경색 , 빈혈 , 설사 , 간염 , 안구 천공 등
상품명 Tarceva
개발회사 Roche
N
N
NH
OO
OO
Lapatinib
화학명N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6-[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]quinazolin-4-amine
분류 항악성종양제
적응증 유방암
부작용 심장독성 , 간독성 , 설사 등
상품명 Tykerb
개발회사 GSK
N
N
HN
O
HN
SO
O
O
FCl
Introduction
HDACs comprise a family of 18 genes in humans and are
divided into four classes.
Among them are the Class I (HDAC1-3, 8) and II (HDAC4-
6, 7, 9-10) zinc-containing hydrolases.
HDAC inhibitors can impact a variety of cell functions by
blocking the deacetylation of histone or nonhistone pro-
teins, such as HSP90 and tubulin, causing cell cycle arrest,
differentiation, and/or apoptosis.
Introduction
The HDAC inhibitor vorinostat (SAHA) is an FDA-approved drug for the
treatment of cutaneous T-cell lymphoma (CTCL).
In our own study, vorinostat and erlotinib were used to achieve HDAC
inhibition. respectively, and a well-established mathematical model for
studying multidrug interactions was applied to assess whether there is a
synergistic effect between HDAC inhibition.
Here, we describe the design, synthesis, and structure-activity relation-
ship (SAR) of these novel compounds and the identification of 8 (CUDC-
101) as a clinical candidate currently in phase I clinical trials.
Compound Design
Chemistry
Chemistry
Chemistry
Chemistry
Chemistry
Chemistry
Result & Discussion
Result & Discussion
Result & Discussion
Result & Discussion
Result & Discussion
Result & Discussion
Conclusion
HDAC inhibitors can impact a variety of cell functions by blocking
the deacetylation of histone or non-histone proteins, such as HSP90
and tubulin, causing cell cycle arrest, differentiation, and/or apop-
tosis.
Compound 8 is a potent HDAC inhibitor with favorable drug-like
properties. Therefore, compound 8 has advanced to clinical develop-
ment as a novel anticancer agent.
Non-hydroxamate HDAC InhibitorEnzyme assay
Non-hydroxamate HDAC InhibitorEnzyme assay
Non-hydroxamate HDAC InhibitorEnzyme assay
Hydroxamate type HDAC InhibitorTotal Scheme
S N
O
O
OO
N
O O O O
NH2S(NH4)2S
MeOH, overnight
ethyl bromopyruvate
EtOH, reflux, 1h
Molecular Weight: 259.32Molecular Weight: 163.24Molecular Weight: 129.16
LiOH, H2OAcetone, reflux, 5h
NH
O
S
N O
F
NH
O
S
N O
F
S N
O
OH
OO
Molecular Weight: 231.27
O
NH
O
S
N O
F
HN OH
NHS, PhI(OAc)2, MeCN, 0°C, 1h
NH2OH, 12h
Molecular Weight: 352.42
Molecular Weight: 278.30 Molecular Weight: 309.32
EDCI, HOBt hydrate4-fluorophenethylamine, TEA
ACN, DMF1M HCl
THF
S N
O
O
OO
N
O O O O
NH2S(NH4)2S
MeOH, overnight
ethyl bromopyruvate
EtOH, reflux, 1h
Molecular Weight: 259.32Molecular Weight: 163.24Molecular Weight: 129.16
LiOH, H2OAcetone, reflux, 5h
NH
O
S
N O
F
NH
O
S
N O
F
S N
O
OH
OO
Molecular Weight: 231.27
O
Molecular Weight: 352.42
Molecular Weight: 278.30
EDCI, HOBt hydrate4-fluorophenethylamine, TEA
ACN, DMF1M HCl
THF
NH
O
S
N
Fethyl acrylateHoveyda 2nd Grubbs Cat.
Toluene, 2d
NH
O
S
NHN
O
OH
KOH, MeOH
Molecular Weight: 335.35
NH
O
S
N
Molecular Weight: 348.39
O
O
F F
Molecular Weight: 276.33
NH2OH,HClNH2OH solution
CH3P(C6H5)3Br, LiHMDS, PhMe, THF, 0°C,1h
THF, -78°C, 18h
NH
N
HN
O
OOH
S
NH
N
HN
O
OOH
S
NH
N
O
S
NH
O OH
NH
N
O
S
NH
O OH
NH
N
O
S
NHOHO
F
F
F
F
F
NH O
O
N
SHN N
SO
O
F FNH OH NH OH
NH
N O
O
S
F
HN OH
Thank you