How are potential "best-in-class" estrogen receptor degradants "made"?

Breast cancer is the most common cancer among women in the world, and it is also one of the leading causes of cancer deaths

So how did this potential "best-in-class" SERD come about? Recently, the R&D team from Genentech published the development process of GDC-9545 in the Journal of Medicinal Chemistry

The researchers pointed out that although the first SERD fulvestrant was approved for the first time in 2002, the limitations of its patented features allow it to be administered only by intramuscular injection, which limits its binding and efficacy to the target

First, the research team identified a candidate compound that exhibits high activity in in vitro antagonism, degradation and inhibition of proliferation tests, and has good oral availability12

Further optimization produced candidate compounds 33 and 35, which have the strongest degradation efficiency, while achieving a good balance between activity and druggability

Picture source: reference [1]

Based on the crystal structure of 35 and ERa, the researchers fine-tuned 35 and developed more candidate compounds

In the detection of a variety of animal models, 35 not only showed good activity, but also showed good in vitro and in vivo safety

Note: The original text has been deleted

Reference materials:

[1] Liang et al.

[2] Shao (2021).