NIBR-LTSi is a highly selective, active-site binding LATS kinase inhibitor displayed an IC50 of 2.16µM. Since LATS kinases are direct negative regulators of YAP activity, NIBR-LTSi has good oral bioavailability and favorable pharmacokinetic (PK) profile enable YAP activation in vivo[1].
In vitro, HEK293A cells were treated with 5µM NIBR-LTSi for 24 hours increased YAP nuclear translocation, reduced YAP phosphorylation, and enhanced the expression of YAP target genes (CYR61, CTGF, ANKRD1). NIBR-LTSi treatment also increased cell proliferation[1]. 50µM NIBR-LTSi were included in mouse explant cultures and incubated for 24h. NIBR-LTSi treatment activates YAP in basal epithelial cells and induced wound healing in some mouse explants cultured in air-liquid interface conditions[2]. NIBR-LTSi (2.5μM) was added to the culture medium of periodontal ligament stem cell (PDLSCs) at passage 20 with senolytics for 3 days. The inhibition of senescence-associated P21 by senolytics were significantly reversed. NIBR-LTSi treatment increased the expression level of the anti-apoptotic gene BCL2, whereas decreased the expression level of the pro-apoptotic gene BAX[3].
In vivo, NIBR-LTSi oral administrated (100mg/kg) or intravenously injected (1mg/kg) into C57BL/6 mice inhibited YAP phosphorylation in liver tissue, indicating effective LATS inhibition.Treatment of C57BL/6 WT mice with a single dose of NIBR-LTSi(either 30 or 100mg/kg) by oral gavage immediately after partial hepatectomy and monitored proliferation 30 h later. While vehicle-treated mice only showed few proliferating hepatocytes, NIBR-LTSi significantly induced hepatocyte proliferation in a dose dependent manner[1].
References:
[1] Namoto K, Baader C, Orsini V, et al. NIBR-LTSi is a selective LATS kinase inhibitor activating YAP signaling and expanding tissue stem cells in vitro and in vivo. Cell Stem Cell. 2024 Apr 4;31(4):554-569.e17.
[2] Tsissios G, Leleu M, Hu K, et al. Species-specific oxygen sensing governs the initiation of vertebrate limb regeneration. bioRxiv. 2024 Dec;629359
[3] Jia L L, Xiao H, Hao Z H, et al. Senolytic elimination of senescent cells improved periodontal ligament stem cell-based bone regeneration partially through inhibiting YAP. Biochim Biophys Acta Mol Cell Res. 2025 Mar;1872(3):119921.
NIBR-LTSi是一种高选择性的LATS激酶抑制剂，IC50为2.16µM。由于LATS激酶是YAP活性的直接负调节因子，NIBR-LTSi具有良好的口服生物利用度和药代动力学（PK）特性，可在体内激活YAP[1]。
体外实验中，HEK293A细胞经5µM NIBR-LTSi处理24小时后，YAP核转位增加，YAP磷酸化减少，YAP靶基因（CYR61、CTGF、ANKRD1）表达增强。NIBR-LTSi处理还增加了细胞增殖[1]。在小鼠组织培养中加入50µM NIBR-LTSi，孵育24小时。NIBR-LTSi处理激活了基底上皮细胞中的YAP，并在一些培养于气液界面条件下的小鼠组织中诱导了伤口愈合[2]。向第20代牙周韧带干细胞（PDLSCs）的培养基中加入2.5µM NIBR-LTSi，与抗衰老药物共同培养3天。抗衰老药物对衰老相关P21的抑制作用被显著逆转。NIBR-LTSi处理增加了抗凋亡基因BCL2的表达水平，同时降低了促凋亡基因BAX的表达水平[3]。
体内实验中，通过口服（100mg/kg）或静脉注射（1mg/kg）将NIBR-LTSi给予C57BL/6小鼠，在肝脏组织中抑制了YAP的磷酸化，表明LATS被有效抑制。对C57BL/6野生型小鼠进行部分肝切除术后，立即通过口服给予单剂量NIBR-LTSi（30或100mg/kg），并在30小时后监测增殖情况。与给予载体的小鼠相比，NIBR-LTSi显著以剂量依赖性方式诱导肝细胞增殖[1]。