PF-04620110 is an orally active, selective diacylglycerol acyltransferase-1 (DGAT1) inhibitor (IC50 = 19nM) [1]. PF-04620110 blocks triglyceride synthesis by inhibiting DGAT-1, thereby lowering plasma triglyceride levels in vivo [2]. PF-04620110 is commonly used to treat diabetes [3-4].
In MDA-MB-231 cells, PF-04620110 (5µM; 24h) blocks the conversion of diacylglycerol to triacylglycerol to inhibit lipid droplet formation [5]. In MCF10CA1a cells, PF-04620110 (50µM; 24h) reduces triacylglycerol storage and restricts cell migration [6].
In high-fat diet mice model, PF-04620110 (3mg/kg; po; 4 weeks) suppressed fatty acid induced NLRP3 inflammasome activation [7]. In high-fat diet cynomolgus monkeys model, PF-04620110 (0.1-1mg/kg; po; 4d) treatment induced diarrhea [8].
References:
[1]. Dow R L, Li J C, Pence M P, et al. Discovery of PF-04620110, a potent, selective, and orally bioavailable inhibitor of DGAT-1[J]. ACS medicinal chemistry letters, 2011, 2(5): 407-412.
[2]. Dow R L, Andrews M, Aspnes G E, et al. Design and synthesis of potent, orally-active DGAT-1 inhibitors containing a dioxino [2, 3-d] pyrimidine core[J]. Bioorganic & medicinal chemistry letters, 2011, 21(20): 6122-6125.
[3]. Dow R L, Andrews M P, Li J C, et al. Defining the key pharmacophore elements of PF-04620110: discovery of a potent, orally-active, neutral DGAT-1 inhibitor[J]. Bioorganic & Medicinal Chemistry, 2013, 21(17): 5081-5097.
[4]. Enayetallah A E, Ziemek D, Leininger M T, et al. Modeling the mechanism of action of a DGAT1 inhibitor using a causal reasoning platform[J]. PloS one, 2011, 6(11): e27009.
[5]. Almanza A, Mnich K, Blomme A, et al. Regulated IRE1α-dependent decay (RIDD)-mediated reprograming of lipid metabolism in cancer[J]. Nature communications, 2022, 13(1): 2493.
[6]. Andolino C, Cotul E K, Xianyu Z, et al. Fatty acid synthase-derived lipid stores support breast cancer metastasis[J]. Cancer & metabolism, 2025, 13(1): 35.
[7]. Jo S I, Bae J H, Kim S J, et al. PF-04620110, a potent antidiabetic agent, suppresses fatty acid-induced NLRP3 inflammasome activation in macrophages[J]. Diabetes & Metabolism Journal, 2019, 43(5): 683.
[8]. Cheng D, Zinker B A, Luo Y, et al. MGAT2 inhibitor decreases liver fibrosis and inflammation in murine NASH models and reduces body weight in human adults with obesity[J]. Cell Metabolism, 2022, 34(11): 1732-1748. e5.
PF-04620110是一种口服有效的选择性二酰甘油酰基转移酶-1（DGAT1）抑制剂（IC50 = 19nM） [1]。PF-04620110通过抑制DGAT-1来阻断甘油三酯的合成，从而降低体内血浆甘油三酯水平 [2]。PF-04620110常用于治疗糖尿病 [3-4]。
在MDA-MB-231细胞中，PF-04620110（5µM; 24h）可阻断二酰甘油转化为三酰甘油，从而抑制脂滴形成 [5]。在MCF10CA1a细胞中，PF-04620110（50µM; 24h）可减少三酰甘油的储存并限制细胞迁移 [6]。
在高脂饮食小鼠模型中，PF-04620110（3mg/kg；po；4周）抑制了脂肪酸诱导的NLRP3炎症小体活化 [7]。在高脂饮食食蟹猴模型中，PF-04620110（0.1-1mg/kg；po；4d）治疗诱发腹泻 [8]。