Borussertib is a covalent-allosteric inhibitor of protein kinase Akt with an IC50 of 0.8 nM and a Ki of 2.2 nM for WT Akt.
Borussertib exhibits excellent cellular activity in the nanomolar range. The EC50 values (cell viability assay) of borussertib in AN3CA, T47D, ZR-75-1, MCF-7, BT-474 and KU-19-19 cells are 191 nM, 48 nM, 5 nM, 277 nM, 373 nM and 7770 nM, respectively[1]. Borussertib specifically binds to two non-catalytic cysteines in AKT at positions 296 and 310 by decorating allosteric ligands with electrophilic warheads at suitable positions, thus enabling the irreversible stabilization of the inactive conformation. Borussertib potently inhibits proliferation of PI3K/PTEN-mutated cell lines[2].
Borussertib reveals a good pharmacokinetic profile with reasonable microsomal stability in human and murine microsomes[1]. PK studies are carried out in mice (2 mg/kg intravenous; 20 mg/kg oral gavage; 20 mg/kg, intraperitoneal), Despite a rather low oral bioavailability (<5%), reaching only a maximum plasma concentration of 78 ng/mL (0.13 ?M), There is a significantly higher bioavailability upon intraperitoneal administration (39.6%), with maximum plasma levels of 683 ng/mL (1.14 ?M)[2].
[1] Uhlenbrock N, et al. Chem Sci. 2019, 10(12):3573-3585. [2] Weisner J, et al. Cancer Res. 2019, 79(9):2367-2378.