PHT-427

PHT-427 is a small molecule inhibitor targeting the pleckstrin homology (PH) domains of both PDPK1 (phosphoinositide-dependent kinase-1) and Akt (protein kinase B), key proteins in the PI3K/Akt signaling pathway involved in cancer cell proliferation and survival. It binds with high affinity to the PH domains of these kinases, blocking their activation, leading to downstream inhibition of Akt phosphorylation and PDPK1 signaling, and reduced phosphorylation of their effectors such as p70S6K and GSK3β. PHT-427 demonstrates antitumor activity in preclinical tumor models, especially in cancers with activating PIK3CA mutations, and shows synergistic effects when combined with paclitaxel (breast cancer) and erlotinib (non-small cell lung cancer). Resistance is observed in tumors with K-Ras mutations. Recent studies also identify PHT-427 as a novel inhibitor of New Delhi metallo-β-lactamase-1 (NDM-1), an enzyme conferring resistance to β-lactam antibiotics in Gram-negative bacteria; it restores meropenem sensitivity in NDM-1 expressing bacteria by acting on zinc ions and key active site residues. Antitumor activity and potential for anticancer formulations (including nanoparticle delivery) have been shown in preclinical models of pancreatic, breast, head and neck, and lung cancers[1][2][3][4][5].

Other names

4-dodecyl-N-(5-(5-(methyl(7-nitrobenzo[c][1,2,5]oxadiazol-4-yl)amino)pentyl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide