Capivasertib

Uses

AZD5363 is used in inhibiting the proliferation of certain tumor cell lines.

Biological Activity

azd5363 is a novel, potent phosphoinositide 3-kinase (pi3k)/akt pathway inhibitor with ic50 value of ~200nm. [1]azd5363 is proved to inhibit castrate resistant prostate cancer (crpc) progression. clusterin (clu) and autophagy will be induced which may work as cytoprotective responses which can affect the downstream pi3k/akt signaling. [2] azd5363 inhibits the growth of a lot of human tumor cells in a dose dependent manner. the mode of action could be monotherapy as well as in combination with her2 inhibitors in breast cancer models. [3] it is suggested to induce cell apoptosis by measuring the expression of parp cleavage, the activity of caspase 3, et al. [1]most importantly, azd5363 can target the pi3k/akt-pathway in vivo significantly, thus reducing the serum psa-levels and tumor volume, finally, it could postpone the progression to crpc.[1]

Synthesis

General steps: 1. N,N-diisopropylethylamine (1.676 mL, 9.62 mmol) was added under nitrogen protection to a solution containing (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (1 g, 3.21 mmol) and 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (0.493 g 3.21 mmol) in a solution of n-butanol (15 mL). 2. The reaction mixture was stirred at 60 °C for 18 hours. 3. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (50 mL) and washed sequentially with water (25 mL) and saturated saline (25 mL). 4. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the crude product. 5. The crude product was purified by fast silica gel column chromatography using dichloromethane with a gradient elution containing 0 to 6% methanol and ammonia. 6. The purified fraction was collected and concentrated to dryness under reduced pressure to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (842 mg) as a white foamy solid. 7. The resulting product was dissolved in ethyl acetate (7 mL) and stirred for 18 hours. 8. The precipitated solid was collected by filtration, washed with a small amount of ethyl acetate and dried in a vacuum oven at 55 °C for 18 h. (S)-4-Amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (0.585 g, 42.5% yield) was obtained as a white solid. Mass spectrum (electrospray positive ion mode): m/z (ES+) (M + H)+ = 429; HPLC retention time tR = 1.60 min. 1H NMR (400.13 MHz, DMSO-d6) δ 1.39-1.47 (2H, m), 1.80-2.02 (4H, m), 2.17 (2H, s), 3.35-3.40 (2H, m), 3.50-3.59 (2H, m), 4.34-4.41 (2H, m), 4.53 (1H, t), 4.88 (1H, d), 6.57 (1H, m), 7.14-7.16 (1H, m), 7.31-7.37 (4H, m), 8.12 (1H, s), 8.42 (1H, d), 11.62 (1H, s).

in vivo

target

Akt

IC 50

Akt1: 3 nM (IC₅₀); Akt2: 7 nM (IC₅₀); Akt3: 7 nM (IC₅₀); P70S6K: 6 nM (IC₅₀); PKA: 7 nM (IC₅₀); ROCK2: 60 nM (IC₅₀); ROCK1: 470 nM (IC₅₀); Autophagy

storage

Store at -20°C

References

[1] thomas c, crafter c, davies b, zoubeidi a, gleave me. azd5363, a novel akt inhibitor, delays prostate cancer progression. the journal of urology. may 2011. 185(4s): e292-293.
[2] kumano m, zhang f, shiota m, crafter c, davies b, zoubeidi a, gleave m. clusterin knockdown enhances antitumor activity of a novel akt inhibitor, azd5363, through inhibition of autophagy in prostate cancer. the journal of urology. may 21 2012. e392.
[3] davies br, greenwood h, dudley p, et al. preclinical pharmacology of azd5363, an inhibitor of akt: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background. mol. cancer ther. arp 2012. 11: 873.