XRK3F2

**XRK3F2** is a small-molecule inhibitor developed to selectively target the p62 (SQSTM1) ZZ domain, which mediates signaling involved in NF-κB activation, autophagy, and osteoclastogenesis in the tumor microenvironment. This compound blocks p62-ZZ domain-mediated signaling, disrupting cancer-promoting and bone-destroying processes seen in multiple myeloma (MM). Mechanistically, XRK3F2 blocks the interaction of p62 with key effectors, thereby inhibiting NF-κB activation and autophagic survival of MM cells, reversing MM-induced epigenetic suppression of Runx2 (a key transcription factor for osteoblast differentiation) through prevention of GFI1 and HDAC1/EZH2 recruitment. This results in restored bone formation, osteoblast differentiation, reduced tumor growth, and enhanced efficacy of proteasome inhibitors such as bortezomib. Preclinical data demonstrate XRK3F2's potential both as monotherapy and in combination regimens for MM, with demonstrated effects in vitro and in mouse models[1][3][4][5][6].