Epidermal growth factor receptor Tyrosine kinase inhibitor

Presentation on theme: "Epidermal growth factor receptor Tyrosine kinase inhibitor"— Presentation transcript:

1 Epidermal growth factor receptor Tyrosine kinase inhibitor
Iressa(Gefitinib) Epidermal growth factor receptor Tyrosine kinase inhibitor (EGFR-TKI) 최영재

2 Gefitinib (Iressar) 화학식 ; 4-(3'-chloro-4'-fluoroanilino)-7-methoxy
-6-(3-morpholinopropoxy) quinazoline * 제품명 ; 이레사 정 (IRESSA Tab.) * CAS No 판매사 한국 아스트라제네카 ㈜ 적응증 비소세포폐암 (표적 항암치료제) 허가사항 * 전문의약품 ; 이레사 정 250mg (허가일 ; ) * PMS 만료 ; 효능/효과 * EGFR 활성 변이가 있는 국소 진행성 또는 전이성 비소세포폐암의 1차 치료 * 기존의 화학요법에 실패한 비소세포폐암(수술 불가능 또는 재발한 경우) 용법/용량 * 성인 1일 1회 1정을 경구투여한다. 판매가 정 250mg (\47,892)

3 폐암 정의 및 종류 폐암이란? 폐에 생긴 악성 종양을 말하며, 암세포가 폐를 구성하는 조직에서 발생한 원발성 폐암과 암세포가 다른 기관에서 생겨나 혈관이나 림프관을 타고 폐로 이동해 증식하는 전이성 폐암으로 나눌 수 있다. 폐암 종류 크기와 형태에 따라 비소세포폐암과 소세포폐암으로 구분 비소세포폐암 (Non small cell carcinoma) : 편평상피세포암, 선암, 대세포암 소세포암은 (Small cell carcinoma) : 폐암 환자의 약 15~25%에서 발생하며, 전반적으로 악성도가 강하여 발견 당시 림프관이나 혈액 순환을 통하여 다른 장기나 반대편 폐, 종격동으로 전이되어 있는 상태로 발견되는 경우가 많습니다.

4 표적항암제 신호전달경로 억제제(Signal Transduction Pathway Inhibitor)
:신호전달경로를 활성화 시키는 중요한 매개 효소 Tyrosine kinase, Protein kinase C, Farnesyl transferase등 티로신 키나제(Tyrosine kinase) 길항제 :HER1 수용체로 알려진 인간 상피세포 성장인자 수용체(EGFR, Human Epidermal Growth Factor Receptor)는 네 종류(HER1, HER2, HER3, HER4)가 있으며, 여기에 ‘리간드’라는 물질이 결합하게 되면 티로신 키나제(tyrosine kinase)의 활성 과정을 거친 후, 세포 내로 세포성장신호를 전달하여 이에 따라 암세포의 생존이나 증식, 전이를 일으킵니다.

5 주요 표적 항암제

6 Mechanism of action of tyrosine kinase
Receptor expression at membrane claveola Ligand binding Hetero/homodimerization leading to tyrosine kinase activation and tyrosine transphosphorylation Signal transduction Receptor internalization Receptor degradation or re-expression.

7 Mechanism of action of tyrosine kinase

8 Signaling pathways and inhibitors of EGFR
Fig. 1. Signaling pathways and inhibitors of EGFR. Activation of EGFR leads to homodimerization/heterodimerization, phosphorylation of specific tyrosine residues, and recruitment of several proteins at the intracellular portion of the receptors. Phospholipase Cγ (pink) and STAT transcription factors (blue) bind directly to the receptor, whereas Ras/Raf/MAPK pathway (orange) and PI3K pathway (green) need several specific adaptor molecules (yellow). PI3K can also bind directly any of the erbB partners of EGFR heterodimers.

9 Common approaches for inhibiting EGFR

10

11

12 gefitinib in X-ray structure (red)

13 binding of gefitinib kinase domain of EGFR

14 Bioorganic & Medicinal Chemistry Letters,
11(2001), pp ; Andrew J. Barker .et al. EGF-RTK IC50 : 5nM (in vitro) KB cells : IC50 : 50nM EGF-RTK IC50 : 9nM (in vitro) KB cells : IC50 : 80nM

15 Synthetic Scheme

16 SAR studies(by Astrazeneca)
Potent inhibitor of EGFR-TK (IC50 = 5 nM) But, on orally dosing it appeared to be rapidly metabolised. (half-life apporximately 1h) Small liphophilic E.D.G Free CH at the 2-, 5-, 8- position Bioorg. & Medchem Lett 11 (2001)

17 SAR with 2 carbon atoms and 6-oxygen
IC 50 = 2 nM most potent TKI but low blood concentration

18 SAR with 3 carbon atoms and 6-oxygen
IC 50 = 80 nM Most potent inhibitor of tumor cell growth

19 SAR with 2-hydroxy substituent and 6-oxygen
Compounds with 2-hydroxy substituent generally achieved low blood concentrations.

20 SAR for drug concentration in blood
Drug concentration in blood: 0.1 ~ 0.64 μM imidazol-ethyl derivative (16) morpholino-ethyl derivative (19) : highest concentrations at the 6-h time point 16 19 These compounds sustained a higher concentration at 24h than the parent compound 4.

21 Adventages of ZD 1839(irresa)
In vitro, ZD 1839 is not the most potent compound but, achieves high and sustained blood levels in vivo, over a 24-h period At the 24-h time point, the concentration of drug in blood (5.7 μM) As well as having good oral bioavailability, ZD 1839 inhibits the growth of a broad range of human solid tumor xenografts in a dose-dependent manner.

22 Retrosynthetic analysis of Gefitinib
(AstraZeneca)

23 Scheme

24 Reaction mechanism 1. Monodemethylation

25 2. Acetylation

26 3. Chlorination

27 4. 친핵성 방향족 치환반응