LATS-IN-1 is an inhibitor of LATS1 and LATS2 (IC50 = 2nM for both). Lats-IN-1 inhibits core Hippo pathway kinases and activates downstream effector molecules YAP/TAZ, which translocate to the nucleus, driving expression of genes that promote cell proliferation and survival. Lats-IN-1 is primarily used to treat tissue regeneration and degenerative diseases [1-4].
In HEK293A cells, LATS-IN-1 (10μM, 24h) inhibits phosphorylation of YAP1 in serum-starved HEK293A cells (EC50 = 510 nM) [1]. In K562 cells, LATS-IN-1 (30μM, 48h) significantly reduces the number of K562 colonies in the colony formation assay [5]. In human embryonic stem cells, LATS-IN-1 (30μM, 24h) inhibition of the Hippo Pathway Promotes Growth of ATM-Knockout human embryonic stem cells and of Their Derived NPCs [6]. In MCF-7 cells, the proliferation and migration ability of MCF-7 cells was significantly restored after LATS-IN-1 (30μM, 24h) inhibited the Hippo signaling [7]. In LX2 cells, Lats-IN-1 (5μM, 24h) was supplemented, expression of YAP and α-SMA was increased in Ctrl (scrambled)-siRNA-transfected LX2 cells [8].
In a subcutaneous xenograft tumor mouse model of 4T1 cells, LATS-IN-1 (10mg/kg, sc, 7d) increases xenograft tumor growth [7]. In myocardial infarction mice models, Lats-IN-1 (1mg/kg, ip, 14d) treated mice had higher ejection fraction (EF%) and fractional shortening (FS%) than those treated with the vehicle [9]. In lumbar spine instability surgery mice modes Lats-IN-1 (3mg/kg, ip, 56d) treated mice showed less pores or remodeling related signs in the cartilage endplate, with abundant Collagen II expression and rare Collagen X expression [10]. In vascular smooth muscle cell-specific Ddr1 knockout mice, Lats-IN-1 (0.5mg/kg, ip, 7d) abolishes the effect of DDR1-IN-1 on the inhibition of YAP activation [11].
References:
[1]. Kastan N, Gnedeva K, Alisch T, et al. Small-molecule inhibition of Lats kinases may promote Yap-dependent proliferation in postmitotic mammalian tissues. Nature communications. 2021 May 25; 12(1): 3100.
[2]. Cai X, Warburton C, Perez OF, et al. Hippo signaling modulates the inflammatory response of chondrocytes to mechanical compressive loading. bioRxiv. 2023 Jun 11.
[3]. Boopathy GT, Hong W. Role of hippo pathway-YAP/TAZ signaling in angiogenesis. Frontiers in cell and developmental biology. 2019 Apr 10; 7: 49.
[4] Ohnishi Y, Masui A, Suezawa T, et al. Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells. Stem cell reports. 2024 Apr 9; 19(4): 529-544.
[5]. Klaihmon P, Lorthongpanich C, Kheolamai P, et al. Inhibition of LATS kinases reduces tumorigenicity and increases the sensitivity of human chronic myelogenous leukemia cells to imatinib. Scientific Reports. 2024 Feb 18; 14(1): 3993.
[6]. Viner-Breuer R, Golan-Lev T, Benvenisty N, et al. Genome-Wide Screening in Human Embryonic Stem Cells Highlights the Hippo Signaling Pathway as Granting Synthetic Viability in ATM Deficiency. Cells. 2023 May 29; 12(11): 1503.
[7]. Chen Y, Li J, Pu L, et al. DNAJB4 suppresses breast cancer progression and promotes tumor immunity by regulating the Hippo signaling pathway. Discover Oncology. 2023 Aug 7; 14(1): 144.
[8]. Xie L, Chen H, Zhang L, et al. JCAD deficiency attenuates activation of hepatic stellate cells and cholestatic fibrosis. Clinical and Molecular Hepatology. 2024 Jan 8; 30(2): 206.
[9]. Shen H, Wang Q, Liu B, et al. Lats-IN-1 protects cardiac function and promotes regeneration after myocardial infarction by targeting the hippo pathway. Frontiers in Pharmacology. 2024 Oct 3; 15: 1463465.
[10]. Li H, Tang Y, Liu Z, et al. Lumbar instability remodels cartilage endplate to induce intervertebral disc degeneration by recruiting osteoclasts via Hippo-CCL3 signaling. Bone Research. 2024 May 30; 12(1): 34.
[11]. Liu J, Wang J, Liu Y, et al. Liquid-liquid phase separation of DDR1 counteracts the hippo pathway to orchestrate arterial stiffening. Circulation Research. 2023 Jan 6; 132(1): 87-105.
LATS-IN-1是LATS1和LATS2的抑制剂（IC50均为2nM）。Lats-IN-1抑制核心Hippo通路激酶，并激活下游效应分子YAP/TAZ，使其转位至细胞核，从而驱动促进细胞增殖和存活的基因表达。Lats-IN-1 主要用于治疗组织再生和退行性疾病 [1-4]。
在HEK293A细胞中，LATS-IN-1（10μM，24h）可抑制血清饥饿HEK293A细胞中YAP1的磷酸化（EC50 = 510nM） [1]。在K562细胞中，LATS-IN-1（30μM，48h）在集落形成实验中显著减少K562细胞集落的数量 [5]。在人类胚胎干细胞中，LATS-IN-1（30μM，24h)抑制Hippo通路可促进ATM基因敲除的人类胚胎干细胞及其衍生的NPC的生长 [6]。在MCF-7细胞中，LATS-IN-1（30μM，24h）抑制Hippo信号通路后，MCF-7细胞的增殖和迁移能力显著恢复 [7]。在LX2细胞中，补充Lats-IN-1（5μM，24h）后，Ctrl(scrambled)-siRNA转染的LX2细胞中YAP和α-SMA的表达增加 [8]。
在4T1细胞皮下移植瘤小鼠模型中，LATS-IN-1（10mg/kg，ip，7d）可促进异种移植肿瘤的生长 [7]。在心肌梗死小鼠模型中，Lats-IN-1（1mg/kg，ip，14d）治疗小鼠的射血分数（EF%）和缩短分数（FS%）均高于对照组[9]。在腰椎不稳手术小鼠模型中，Lats-IN-1（3mg/kg，ip，56d）治疗小鼠的软骨终板孔隙或重塑相关征象减少，II型胶原蛋白表达丰富，X型胶原蛋白表达稀少 [10]。在血管平滑肌细胞特异性Ddr1基因敲除小鼠中，Lats-IN-1（0.5mg/kg，ip，7d）可消除DDR1-IN-1对YAP活化的抑制作用 [11]。