Transcriptional regulation of steroid hormone receptors

prostate cancer therapeutics

steroid receptors

bind to steroid ligands and function as transcription factors

binding induces conformational change → dimerisation

estrogen & androgen/progesterone

antiestrogens

antagonists that block binding/dimerisation/coactivator binding → change protein conformation unfavorably

chemotherapeutics

ex. tamoxifen

steroidal conjugates

steroids attached to stable peptoid backbones

dense display of steroid ligands → multivalency (molecular velcro)/ avidity

backbone - steric blockade

prostate cancer

5 yr survival rate - 99%

easier to treat in early stages - eponentially more diifuclt at late stages

antiandrogens

ex. biclalutamide, ethisterone

MPC309

ethisterone steroidal conjugate - high affinity AR ligand/partial antagonist activity

bind both monomeric proteins and keep them apart

inhibits prostate cancer in mouse models - dose dependent effect (5mg/kg - 50mg/kg) - appears to also be non-toxic