1. Discovery of 7-(4-(3-Ethynylphenylamino)-7- methoxyquinazolin-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

2. Contents  Vorinostat, Erlotinib, Lapatinib  Introduction  Compound Design  Chemistry (Synthesis)  Result&Discussion  Non-hydroxamate type HDAC Inhibitor Enzyme assay  Hydroxamate type HDAC Inhibitor

3. SAHA(Vorinostat) 화학명 N-hydroxy-N'-phenyl-octanediamide 분류항악성종양제 적응증 두 가지의 전신요법을 사용중이거나 사용한 후, 진행성이거나 지속성 또는 재 발성인 피부 T 세포 림프종 부작용설사, 구역, 식욕부진, 폐색전증, 빈혈 등 상품명 Zolinza 개발회사 Merck

4. Erlotinib 화학명 N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4-amine 분류항악성종양제 적응증비소세포폐암, 췌장암 부작용폐독성, 심근경색, 빈혈, 설사, 간염, 안구 천공 등 상품명 Tarceva 개발회사 Roche

5. Lapatinib 화학명 N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6- [5-[(2-methylsulfonylethylamino)methyl]-2-furyl] quinazolin-4-amine 분류항악성종양제 적응증유방암 부작용심장독성, 간독성, 설사 등 상품명 Tykerb 개발회사 GSK

6. 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, causing cell cycle arrest, differentiation, and/or apoptosis.

7. 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.

8. Compound Design

9. Chemistry

15. Result & Discussion

21. 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.

22. Non-hydroxamate HDAC Inhibitor Enzyme assay

25. Hydroxamate type HDAC Inhibitor Total Scheme

28. Thank you