Mechanisms of Action

The androgen receptor signaling pathway is the primary pathway that drives prostate cancer growth and has been implicated in other hormonally driven diseases. The pathway is ordinarily activated by the binding of androgens, such as testosterone and DHT, to the ligand binding domain of androgen receptors in prostate cancer cells.

Galeterone disrupts the activation of the pathway through multiple mechanisms of action, which has been demonstrated in multiple preclinical, clinical and ongoing clinical studies:

inhibition of the enzyme CYP17, which blocks the synthesis of testosterone;
androgen receptor antagonism, which blocks the binding of testosterone or DHT with the androgen receptor; and
androgen receptor degradation, which reduces the amount of androgen receptor protein in the tumor cells.

CYP17 Lyase Inhibition

Galeterone is an inhibitor of CYP17, a protein with two enzymatic functions: hydroxylase and lyase. Because CYP17 plays a central role in synthesizing the androgens that drive tumor cell growth, CYP17 inhibitors have been developed to treat patients with CRPC. Selectively blocking CYP17 lyase reduces the production of key androgen precursors. However, inhibition of the CYP17 hydroxylase causes an accumulation of certain steroids, such as progesterone, deoxycorticosterone and corticosterone, and a reduction in cortisol, which can result in mineralocorticoid excess. An ideal CYP17 inhibitor will selectively block the lyase function of CYP17 relative to hydroxylase so that these steroids do not accumulate to the extent that they cause mineralocorticoid excess. In preclinical studies, galeterone was shown to selectively block the lyase function of CYP17 relative to the hydroxylase function. This is consistent with clinical trial results that show that galeterone has not caused mineralocorticoid excess and, as a result, does not require co-administration of steroids.

Androgen Receptor Antagonist

Galeterone blocks androgens from binding to the androgen receptor. This results in reduced translocation of the androgen receptor into the cell nucleus, which prevents the androgen receptor from acting as a transcription factor and decreases the expression of androgen-responsive genes that drive tumor growth.

Androgen Receptor Degradation

Galeterone decreases the amount of androgen receptor protein in prostate tumor cells by enhancing degradation of the androgen receptor. This reduces the number of androgen receptors in the tumor cells to which androgen can bind and decreases the sensitivity of androgen responsive cells to androgens. Tokai has observed this effect of galeterone in varying degrees in prostate cancer cell lines that express non- mutated full-length androgen receptors and multiple forms of androgen receptor alterations. These alterations include splice variants, such as AR-V7, that are missing large portions of the protein sequence of the androgen receptor in the C-terminus and point mutations, which are single amino acid mutations in the protein sequence of the androgen receptor. To Tokai’s knowledge, there are no approved drugs or drugs in clinical development, other than galeterone, with the mechanism of action of androgen receptor degradation.