PHD-2 Activation to Stabilize HIF-1α and FASN in Mammary Gland Cancer

Abstract

Activation of prolyl hydroxylase-2 (PHD2) has emerged as an attractive target to counteract tumor hypoxia and thereby uncontrolled cellular proliferation. We utilized an integrated strategy to identify new PHD2 activators using series of in silico tools and in vitro methods. The in silico screening helped to identify 4-ethyl-3-(4-methoxyphenyl)-2,2-dimethyl-2H-chromen-7-yl acetate (BBAP-3), [4-(7-acetyloxy-4-ethyl-2,2-dimethylchromen-3-yl)phenyl]acetate (BBAP-4), 3-(4-methoxyphenyl)-2,2,4-trimethyl-2H-chromen-7-yl acetate (BBAP-5) as an activator, who are structurally similar to KRH102140 (a known activator of PHD2). All BBAP-3, BBAP-4, and BBAP-5 were docked with enzyme PHD2. The binding energy of BBAP-3, BBAP-4, and BBAP-5 were recorded as -3.92 Kcal/mol, -3.57 Kcal/mol, and -4.59 Kcal/mol, respectively as well as all three compounds were also observed to be nonmutagenic with sufficiently high oral LD50 when evaluated through toxicity estimation software tool. The IC50 of BBAP-3, BBAP-4, and BBAP-5 were determined against tamoxifen. The BBAP-3, BBAP-4 and BBAP-5 drug did not cross 50% inhibition after 25 µM and there was also no linearity in a dose-dependent manner therefore not considered for further evaluation.

Keywords: fatty acid synthase, breast cancer, hypoxia-inducible factor, prolyl hydroxylase-2 (PHD2)

Cite this Article Devi U, Gupta PS. PHD-2 Activation to Stabilize HIF-1α and FASN in Mammary Gland Cancer. Research & Reviews: A Journal of Toxicology. 2018; 8(3): 28–33p.