Discovery of AZD3514, a small-molecule androgen receptor downregulator for treatment of advanced prostate cancer

AZD3514: A Small Molecule That Modulates Androgen Receptor Signaling and Function In Vitro and In Vivo

“…Further details of instrument set up are included in Supplementary Methods for reference. Both the TSQ Vantage and 4000 QTRAP were operated in SRM mode to selectively measure the following AR peptides: GAFQNLFQSVR (21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) and LLDSVQPIAR (862-871). The unlabeled, "heavy" labeled ( 13 C 6 , 15 N 4 R, þ10 Da), and "medium" labeled ( 13 C 6 , þ6 Da) forms of both peptides were measured in parallel.…”

“…Details relating to the identification of AZD3514 compound have been recently described (29) The ability of AZD3514 to inhibit AR function was assessed in LNCaP and LAPC4 prostate cancer cells that express the T877A ligand-binding domain mutation of AR and wild-type AR, respectively (33,34). AZD3514 and AR antagonist enzalutamide inhibited DHT-driven proliferation of LNCaP cells in a dose-dependent manner ( Fig.…”

“…[4,3-b]pyridazine (AZD3514; AstraZeneca; Fig. 1) was synthesized according to the published procedures (29). For in vivo studies, AZD3514 was formulated in a solution of 20% Captisol (b-cyclodextrin sulfobutyl ethers sodium salts) at pH 4.…”

Novel tactics for designing water-soluble molecules in drug discovery

“…In this regard, minor changes can have a very large effect on solubility. For example, although 27 and 28 differ by only 2 hydrogen atoms, there is > 100-fold difference in aqueous solubility (sol 7.4 = 5.4 and 577 p M, respectively), a large portion of which comes from 27 having a log D 7.4 of 2.5 versus 3.2 for 28 which reflects an expected increase in basicity and hydrogen-bond acceptor basicity [48]. A more dramatic structural change involves the g-secretase inhibitors 29 and 30 [49].…”

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer – results of two parallel first-in-human phase I studies

“…AZD3514 (AstraZeneca, Macclesfield, UK) is a first-in-class, orally bio-available drug that inhibits androgen-dependent and AR-independent signalling through two distinct mechanisms; inhibition of ligand-driven nuclear AR translocation and down-regulation of AR levels (selective androgen receptor down-regulator, SARD) [15,16]. AZD3514 binds to the AR ligand-binding domain (LBD) with an IC 50 of 23 μM but has no measurable binding property (>100 μM) to other nuclear hormone receptors.…”