PALB2 Activators

PALB2 activators are a suite of chemical compounds that enhance the functional activity of PALB2 by manipulating various DNA damage response pathways to increase the reliance on homologous recombination (HR), a process critical for maintaining genomic integrity. PARP inhibitors such as Olaparib, Rucaparib, and Talazoparib, function by inhibiting poly (ADP-ribose) polymerase, an enzyme instrumental in repairingsingle-strand breaks. This inhibition leads to the persistence of DNA lesions, which are then channeled into double-strand breaks, necessitating the resolution via HR wherein PALB2 facilitates the localization and stabilization of BRCA2 at DNA damage sites. DNA-PK inhibitors such as NU7026 and Wortmannin, as well as PI3 kinase inhibitor LY294002, restrict non-homologous end joining (NHEJ), a competing pathway, thereby upscaling the HR pathway's involvement and indirectly enhancing PALB2's activity.

In addition to these, ATM kinase inhibitors like KU-55933 and KU-60019, along with the dual ATM and ATR kinase inhibitor CGK733, exacerbate the cellular need for HR by dampening the DNA damage response, which in turn heightens the functional necessity of PALB2 in DNA repair. SCR7, by specifically targeting ligase IV, also shifts the cellular preference towards HR for DNA repair, further spotlighting the significance of PALB2. The orchestrated effects of these compounds converge on the promotion of HR, a pathway where PALB2 is not just a participant, but a keystone molecule, thus ensuring the enhancement of PALB2's activity without altering its expression or directly modifying its function. Collectively, these activators underline the indispensability of PALB2 in cell survival and genome maintenance by orchestrating a cellular environment that is heavily reliant on the HR pathway, thereby potentiating the biological role of PALB2.