SBI-0206965

SBI-0206965 , the pyrimidine derivative , is a highly selective kinase ULK1 inhibitor with an IC₅₀ value of 108nM^[1]. SBI-0206965 was reported as a small-molecule inhibitor of kinase ULK2 , which has an IC₅₀ value as 711nM^[2]. SBI-0206965 can also inhibit AMPK^[3]. 

SBI-0206965 (25μM , 3h) modestly inhibited AMPK signalling in C2C12 myotubes, but also inhibited Insulin signalling , Insulin-mediated/AMPK-independent glucose uptake^[4]. SBI-0206965 (10μM , 40min) has a non-specific off-target inhibitory effect on muscle glucose transport^[2]. SBI-0206965 ( 8μmol/L , 1h) reversed hypoxia/reoxygenation (H/R)-induced cell death and pyroptosis in cardiomyocytes^[5] .

SBI-0206965 (50mg/kg ; 3 days , 9 times in 30 days ; intraperitoneal injection) triggered apoptosis by preventing autophagy and pentose phosphate pathway (PPP) flux^[6] . SBI-0206965 ( 5 or 50μM ; 2.5h ; intravitreal injections , optic nerve live imaging) protects against acute axonal degeneration (AAD) after rat optic nerve crush in vivo^[7] .

SBI-0206965 suppressed 5-aminoimidazole-4-carboxamideribo nucleotide(AICAR) stimulated glucose transport in both the extensor digitorum longus and soleus muscle ^[2] .

References:

[1] CHEN Y, XIE X, WANG C, et al. Dual targeting of NUAK1 and ULK1 using the multitargeted inhibitor MRT68921 exerts potent antitumor activities [J]. Cell Death Dis, 2020, 11(8): 712.

[2] KNUDSEN J R, MADSEN A B, PERSSON K W, et al. The ULK1/2 and AMPK Inhibitor SBI-0206965 Blocks AICAR and Insulin-Stimulated Glucose Transport [J]. Int J Mol Sci, 2020, 21(7):

[3] DITE T A, LANGENDORF C G, HOQUE A, et al. AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI-0206965 [J]. J Biol Chem, 2018, 293(23): 8874-85.

[4] AHWAZI D, NEOPANE K, MARKBY G R, et al. Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965 [J]. Biochem J, 2021, 478(15): 2977-97.

[5] DENG L, JIANG L, WEI N, et al. Anesthetic sevoflurane simultaneously regulates autophagic flux and pyroptotic cell death-associated cellular inflammation in the hypoxic/re-oxygenated cardiomyocytes: Identification of sevoflurane as putative drug for the treatment of myocardial ischemia-reperfusion injury [J]. Eur J Pharmacol, 2022, 936(175363.

[6] LU J, ZHU L, ZHENG L P, et al. Overexpression of ULK1 Represents a Potential Diagnostic Marker for Clear Cell Renal Carcinoma and the Antitumor Effects of SBI-0206965 [J]. EBioMedicine, 2018, 34(85-93.

[7] VAHSEN B F, RIBAS V T, SUNDERMEYER J, et al. Inhibition of the autophagic protein ULK1 attenuates axonal degeneration in vitro and in vivo, enhances translation, and modulates splicing [J]. Cell Death Differ, 2020, 27(10): 2810-27.

SBI-0206965，这种嘧啶衍生物是一种高选择性的激酶ULK1抑制剂，IC₅₀值为108nM^[1]。SBI-0206965亦是ULK2激酶的小分子抑制剂，IC₅₀值为711nM^[2]。SBI-0206965也能抑制AMPK^[3]。

SBI-0206965（25μM，3小时）适度抑制C2C12肌管中的AMPK信号传导，但也抑制胰岛素信号传导、胰岛素介导/与AMPK无关的葡萄糖摄取^[4]。SBI-0206965（10μM，40分钟）对肌肉葡萄糖转运具有非特异性脱靶抑制作用^[2]。

SBI-0206965（8μmol/L，1小时）可逆转缺氧/再氧化（H/R）诱导的心肌细胞死亡和焦亡^[5]。SBI-0206965(50毫克/公斤；3天，30天9次；腹腔注射)通过阻止自噬和戊糖磷酸途径（PPP）进行而引发细胞凋亡^[6]。SBI-0206965(5或50μM；2.5小时；玻璃体内注射（视神经实时成像）对视神经挤压后急性轴突变性（AAD）的体内保护作用^[7]。 

SBI-0206965抑制了伸趾长肌和腓肠肌中5-氨基咪唑-4-羧酰胺核糖核苷酸（AICAR）刺激的葡萄糖转运^[2]。