XMU-MP-8 (SKPer1) is a potent molecular glue degrader that targets the oncogenic protein SKP2. It interacts with the F-box domain of SKP2 (Kd≈ 36 μM) and the N-terminal TPR domain of the E3 ligase STUB1 (Kd≈ 2.5 μM), leading to the formation of a stable SKP2-SKPer1-STUB1 ternary complex (Kd≈ 8.9 nM). This interaction triggers the ubiquitination and proteasomal degradation of SKP2. XMU-MP-8 selectively eradicates cancer cells expressing SKP2 and exhibits notable tumor-suppressive effects in vivo along with a favorable safety profile. It is applicable in research on cancers such as non-small cell lung adenocarcinoma (NSCLC) and prostate adenocarcinoma.

SKP2:36 μM (Kd)

XMU-MP-8 specifically induces a cell survival phenotype in the SKP2-F-C cell line at a concentration of 10 μM for 24 hours while showing no such effects in other F-C cell lines, eliminating the likelihood of general interference with F-C death protein activation. When applied at 1-10 μM for 0-24 hours, XMU-MP-8 triggers ubiquitination and proteasomal degradation of SKP2, shortening its half-life and depleting endogenous SKP2 protein without affecting mRNA levels. Over 72 hours, XMU-MP-8 inhibits the proliferation of SKP2-overexpressing cancer cells, with IC50 values of 3.7 μM for PC-3, 6.7 μM for A549, 3.7 μM for JHH-7, 6.2 μM for SW620, 4.5 μM for LoVo, 6.9 μM for RKO, 5.6 μM for Caco2, and 5.3 μM for HeLa. At 10 μM for 72 hours, XMU-MP-8 completely halts proliferation and induces massive cell death in SKP2-overexpressing cell lines. It induces SKP2 protein degradation and p27 protein accumulation in SKP2 high-expression cell lines (JHH-7 and PC-3) within 24 hours, but shows no significant effects in SKP2 low-expression cell lines (IMR-90 and MCF-10A). Additionally, XMU-MP-8, at concentrations ranging from 2.5 to 10 μM over 0-5 days, has no significant impact on the growth of normal mouse intestinal organoids or human peripheral blood mononuclear cells. In 2.5 hours at 10 μM, XMU-MP-8 enhances the SKP2-STUB1 interaction by 122 times through recruitment of the E3 ligase STUB1 to SKP2's F-box domain, forming a ternary complex that leads to SKP2 ubiquitination and degradation.

XMU-MP-8, administered intravenously at doses of 15 and 30 mg/kg once daily for 14 days, demonstrates significant antitumor activity by degrading SKP2 in A549 and PC-3 xenograft mouse models. Moreover, at a dose of 30 mg/kg, given under the same conditions, it shows no adverse effects in BALB/c nude mice.