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Discovery of 7-(4-(3-Ethynylphenylamino)-7methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide
(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)
화학명
분류
N-hydroxy-N'-phenyl-octanediamide
항악성종양제
적응증
두 가지의 전신요법을 사용중이거나 사용한 후, 진행성이거나 지속성 또는
재발성인 피부 T세포 림프종
부작용
설사, 구역, 식욕부진, 폐색전증, 빈혈 등
상품명
Zolinza
개발회사
Merck
Erlotinib
화학명
분류
N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)
quinazolin-4-amine
항악성종양제
적응증
비소세포폐암, 췌장암
부작용
폐독성, 심근경색, 빈혈, 설사, 간염, 안구 천공 등
상품명
Tarceva
개발회사
Roche
Lapatinib
화학명
분류
N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5-[(2-methylsulfonylethylamino)methyl]-2-furyl]
quinazolin-4-amine
항악성종양제
적응증
유방암
부작용
심장독성, 간독성, 설사 등
상품명
Tykerb
개발회사
GSK
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 proteins,
such
as
HSP90
and
tubulin,
differentiation, and/or apoptosis.
causing
cell
cycle
arrest,
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 relationship (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 apoptosis.
 Compound 8 is a potent HDAC inhibitor with favorable drug-like
properties. Therefore, compound 8 has advanced to clinical development as
a novel anticancer agent.
Non-hydroxamate HDAC Inhibitor
Enzyme assay
Non-hydroxamate HDAC Inhibitor
Enzyme assay
Non-hydroxamate HDAC Inhibitor
Enzyme assay
Hydroxamate type HDAC Inhibitor
Total Scheme
Thank you