SBP-5147

SBP-5147 is an orally active ULK1/ULK2 inhibitor with an IC50 of 2 nM for ULK1 and 53 nM for ULK2. It inhibits the phosphorylation of Beclin-1 and Vps34, reduces autophagy flux, downregulates the expression of ATG13 and ATG101, upregulates MHC-I expression, induces caspase-dependent apoptosis, and decreases the survival rate of non-small cell lung cancer cells. SBP-5147 can be utilized in research related to non-small cell lung cancer[1][2].

ULK2:53 nM

SBP-5147 (Compound 5) binds to ULK1 in HEK293T cells during NanoBRET assays with an IC50 of 47 nM. At 10 μM for 1 hour, it inhibits phosphorylation of ULK1 downstream substrates Beclin-1 (Ser15) and Vps34 (Ser249) by approximately 80% in transfected HEK293T cells. SBP-5147 at 10 μM for 18 hours suppresses autophagic flux in A549 cells under nutrient starvation, reducing high-autophagic flux cell populations. It decreases cell viability in A549, HCC827, H1373, and H1975 cells over 72 hours, with IC50 values of 91, 49, 40, and 35 nM, respectively. At 1 μM for 8-24 hours, SBP-5147 induces caspase-dependent apoptosis in A549 cells. It notably upregulates total MHC-I protein expression in H1373, HCC827, and A549 cells at 15-30 nM over 72 hours. Additionally, SBP-5147 potently inhibits ULK1 kinase activity (IC50 = 2 nM) and ULK2 kinase activity (IC50 = 53 nM) in biochemical ADP-Glo assays. Over 48 hours, it induces degradation of ATG13 in A549 non-small cell lung cancer (NSCLC) cells with an IC50 of 4.5 μM.

Administration of SBP-5147 (10 mg/kg; oral; single dose) in C57BL/6J mice results in reduced levels of ATG13 and ATG101 proteins in liver and lung tissues, indicating its sustained ability to target and inhibit autophagy.