Advances in drug screening methods relative to androgen and estrogen receptors

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1 Chinese Bulletin of Life Sciences Vol. 16, No. 5 Oct., (2004) (, ) ; ; R965.1 A Advances in drug screening methods relative to androgen and estrogen receptors MOU Ling-Yun, WANG Ming-Wei * (The National Center for Drug Screening, Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai , China) Abstract: Androgen and estrogen stimulate cell differentiation and tissue growth through specific interactions with respective receptor ( or ), thereby playing critical roles in numerous physiological processes. Dysfunctions of either hormones or receptors lead to various diseases. Selective or modulators possess ideal pharmacological profiles in disease treatment. Based upon the latest developments in genomics, molecular biology, cellular biology and bioinformatics, etc., new technologies or experimental methods have been applied to screen novel selective or modulators and thus, significantly accelerated the pace of drug discovery. Key words: androgen receptor; estrogen receptor; selective receptor modulator ( androgen receptor ) (estrogen receptor ) ) [1] ( ( ) (1976 ) (1956 ) *

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2 306 (agonist) (antagonist) / (heat shock protein HSP) DBD [5] 1 ; ; (hormone response element HRE) α β DBD [2] HRE [6] N (N-terminal domain NTD) ( binding domain DBD) (ligand binding domain ) (hinge / domain HD)( 1) [3~4] N MAPK K DBD α Ser118 [7~8] C DBD - (activation function AF) AF-1 N ; AF /

3 307 2 [9] α β 5α - 17β - EC50 ( 1) - [10] (selective estrogen receptor modulator SM) SM 1998 [11] 2.1 / 1 / / ( ) ( ) 4- [14~15] - (quantitative structure-activity relationship quantitative structure-activity relationship - QS) (3D 3D QS) Jungblut [16] X [12] [13] Erdos [17] 1970

4 308 / 30 [21~22] c [18~19] α β Metzger [23] Yarbrough CV-1 [23] / CHO HeLa (fluorescent polarization FP) [20] HepG2 LnCaP MCF7 [24~25] (rotation) (tumbling) (fluormone ES1, FES1) FES1 Scatchard 1949 Ki IC50 Ki IC50 β- IC50 (relative binding affinity RBA RBA) IC / β- Metzger [23] c /

5 309 [26~27] - / - Hershberger / (antiandrogen withdrawal syndrome, AWS) Hershberger (prostate-specific antigen, PSA) [28] [31~32] RT-PCR LightCycler [33] [29~30] 50 (prostate binding protein PBP) Northern Northern RT-PCR PBP C3 c PCR mrna / / [34~35] LNCaP 3 /

310 4 3 / QS / / [1]. [A]. [M]. :, 1996. 474~514 [2] Duarte J, Perrière G, Laudet V, et al. NUREBASE: database of nuclear hormone receptors.

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