SIK2

LKB1（肝激酶B1）信号通路已被证明在调节能量稳态、极性和代谢等关键细胞过程中发挥着不可或缺的作用。 LKB1（肝激酶B1）信号通路已被证明在调节能量稳态、极性和代谢等关键细胞过程中发挥着不可或缺的作用。早期研究将LKB1从人类胎肝中分离出来，发现它具有抑癌作用，其突变与遗传性癌症障碍Peutz-Jeghers综合征有关。 进一步的研究确定LKB1是一种主激酶，它通过与CAB39和STRAD支架作用来磷酸化16种下游激酶（AMPK1/2、MARK1/2/3/4、NUAK1/2、SIK1/2/3、BRSK1/2和SNRK），从而对细胞生物学产生影响。尽管LKB1信号轴的部分，如AMPK途径，已经得到了很好的研究和报道，但LKB1直接下游的许多激酶仍然没有得到充分的表征。 图片来源：https://doi.org/10.1016/j.phrs.2023.106757 近日，来自杜兰大学的研究者们在Pharmacol Res.杂志上发表了题为“LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma”的文章，该研究表明LKB1下游的许多激酶对肝癌患者生存率有统计学显著影响。 LKB1、STRAD和CAB39形成一种复合物，其功能是磷酸化和激活下游信号通路。有趣的是，所有复杂成员的mRNA水平都与患者生存率呈正相关，但只有STRADß和CAB39L具有统计学意义。这可以通过LKB1在恶性细胞细胞谢改变中的作用来解释。除了支架蛋白外，具有统计学正生存相关性的下游LKB1激酶是SIK1、SIK2和SNRK。 GEPIA的其他生物信息学分析还发现，与正常肝组织相比，癌症中SIK1的表达减少了2倍。通过蛋白质印迹进行的蛋白质表达分析未能产生任何SIK1条带，进一步支持SIK1在肝细胞癌中的肿瘤抑制作用。此外，SIK3的患者生存风险比范围为0.52-1.03。该值被加权为正相关，但在统计上不显著。 尽管如此，似乎与正生存率有着趋势性的相关性。肝细胞癌细胞系的蛋白质印迹分析显示高表达水平（Huh7和Hep3B）和无表达水平（HepG2和PLC/PRF/5）之间存在明显的二分法，表明存在肝细胞癌亚型的可能性。 相反，AMPKα2、MARK2、BRSK1和BRSK2与肝细胞癌的不良生存结果具有统计学显著相关性。GEPIA分析表明，AMPKα2、BRSK1和BRSK2在正常肝组织中低表达。与正常组织相比，肝脏肿瘤中的AMPKα2和BRSK1分别扩增了5倍和2倍。 免疫印迹分析显示癌症细胞中AMPKα2和MARK2的高水平表达。此外，AMPKα2、MARK2和BRSK2已被证明分别在肝细胞癌、非小细胞肺癌和胰腺癌的营养缺乏条件下通过Warburg效应促进肿瘤活性和生长。 影响肝癌患者生存率的下游激酶。 图片来源：https://doi.org/10.1016/j.phrs.2023.106757 综上所述，STRADß、CAB39L、AMPKα、MARK2、SIK1、SIK2、BRSK1、BRSK2和SNRK的表达对肝癌患者生存率有统计学显著影响。该综述旨在解决下游LKB1激酶在知识方面的差距，并为他们在肝细胞癌发生中的潜在作用奠定基础。（生物谷 Bioon.com） 参考文献 Khoa Nguyen et al. LKB1 Signaling and Patient Survival Outcomes in Hepatocellular Carcinoma. Pharmacol Res. 2023 Apr 4;106757. doi: 10.1016/j.phrs.2023.106757.

来自麻省总医院等机构的科学家们通过研究识别出了一种有潜力的化合物，其或能影响甲状旁腺素信号通路的组分，当给予小鼠口服时，还会增加机体的骨质量。 甲状旁腺素（parathyroid hormone）能刺激骨形成，该激素的类似物也用于治疗骨质疏松症（osteoporosis）患者，然而这些药物只有在每天注射的情况下才会有效。近日，一篇发表在国际杂志Proceedings of the National Academy of Sciences上题为“Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice”的研究报告中，来自麻省总医院等机构的科学家们通过研究识别出了一种有潜力的化合物，其或能影响甲状旁腺素信号通路的组分，当给予小鼠口服时，还会增加机体的骨质量。这一研究发现或有望帮助研究人员开发出预防并治疗骨质疏松症的新型更为方便的药物。 医学博士Marc Wein说道，目前并没有针对骨质疏松症的口服药物来刺激骨形成，于是我们就试图理解正常情况下能控制骨产生的通路，从而开发出诸如此类药物。参与甲状旁腺素的特殊通路或许会抑制盐诱导激酶2和3（SIK2和SIK3），这两种酶类在调节骨生长和重塑方面扮演着重要角色。 新型口服化合物或有望预防并治疗骨质疏松症。 图片来源：Proceedings of the National Academy of Sciences (2022). DOI:10.1073/pnas.2214396119 文章中，研究者Wein及其同事开发了针对这些酶类的新型结构模型，随后利用包括基于结构的药物设计和迭代药物化学等先进方法识别出了能潜在抑制SIK2和SIK3酶类功能的特殊化合物；当给予细胞（尤其是给予小鼠时）时，这种名为SK-124的化合物或许具有甲状旁腺素样的效应；在小鼠机体中，连续三周每天口服治疗一次或能增加机体血液中钙离子和维生素D的水平，同时还会增强机体的骨形成和骨量，同时也并不会产生短期的毒性效应。 研究者指出，基于这些研究发现，我们提出，诸如SK-124等小分子或许能代表新一代的口服骨构建疗法来治疗骨质疏松症；目前研究人员正在与Radius Health公司合作，希望能进一步优化并开发治疗骨质疏松症患者的新型疗法。综上，本文研究结果表明，口服SIK2/SIK3抑制剂SK-124作为疗法进行治疗时或许会对机体骨骼和矿物质代谢产生甲状旁腺素样的效应。（生物谷Bioon.com） 原始出处： Tadatoshi Sato,Christian D. Castro Andrade,Sung-Hee Yoon, et al. Structure-based design of selective, orally available salt-inducible kinase inhibitors that stimulate bone formation in mice, Proceedings of the National Academy of Sciences (2022). DOI:10.1073/pnas.2214396119

FRISCO, Texas, June 24, 2022 /PRNewswire/ -- Green3Bio, a subsidiary of Greenfire Bio , today announced a publication in the Journal of Clinical Investigation1 led by researchers at The University of Texas MD Anderson Cancer Center demonstrating that SIK2 inhibitors, including GRN-300 sensitized ovarian and triple-negative breast cancer (TNBC) cells and xenografts to PARP inhibitors. Zhen Lu, M.D., and Robert Bast, M.D., and colleagues demonstrated that a combination of PARPi and SIKi provides a novel therapeutic approach to enhance PARPi sensitivity in ovarian cancers that initially respond to PARPi and eventually develop drug resistance. The major findings from the preclinical research study include: GRN-300 treatment sensitizes ovarian and breast cancer cells by enhancing olaparib-mediated inhibition of PARP enzyme activity The transcription of DNA repair and apoptosis genes is regulated by SIK2 inhibition by GRN-300 GRN-300 enhances olaparib-induced DNA DSB (double-strand break) and apoptosis Co-administration of GRN-300 and olaparib is synergistic in inhibiting tumor growth in animal models of ovarian cancer and TNBC. These findings provide strong preclinical evidence supporting future clinical trials to determine whether the combination will benefit patients with ovarian and triple negative breast cancers. Animal studies, particularly those with olaparib and GRN-300, did not show significant toxicity based on weight loss. Pre-clinical toxicology studies in rodents and dogs showed no hematologic toxicity, which is particularly important for combination with PARPi. "Patients with ovarian and triple-negative breast cancers are in great need for more effective treatments due to the high prevalence of acquired resistance to standard therapies that involve PARP inhibition," said Steve Morris, MD (Chairperson, Scientific Advisory Board of Greenfire Bio). He added, "The GRN-300 preclinical data published in The Journal of Clinical Investigation shows the potential of GRN-300 and its unique mechanism of action through SIK2/3 inhibition to help change the combination treatment paradigm in gynecologic and breast cancers, irrespective of BRCA mutation status." Ajit Gill, CEO and founder of Greenfire Bio, commented that "This publication provides further support for the development of our clinical asset GRN-300. We believe this agent has the potential to improve treatment of ovarian and other cancers - both as a single agent and in combination with existing therapies such as the PARP inhibitor olaparib that is indicated for the treatment of ovarian and breast cancers under the tradename Lynparza." These data further support the preclinical proof-of-concept for SIK2 inhibitors as potential cancer therapeutics in combination with carboplatin for hard-to-treat ovarian cancer, recently published in Cancers, and they support the continued efforts in our first-in-human clinical trial ongoing at MD Anderson. About Ovarian Cancer According to the American Cancer Society2, ovarian cancer ranks fifth in cancer deaths among women. They estimate that in 2022 there will be about 19,880 new cases of ovarian cancer diagnosed in the United States and that about 12,810 will die of the disease. According to the World Cancer Research Fund International3, there were about 313,000 new cases of ovarian cancer diagnosed worldwide in 2020. Ovarian cancer is difficult to detect at an early, more treatable stage; therefore, the current lack of salvage treatment for women, who experience a recurrence, results in a 5-year survival rate of less than 30%. About GRN-300 GRN-300 (previously ARN3261) is an orally bioavailable first-in-class novel, small molecule, dual inhibitor of the salt-inducible kinases 2 and 3 (SIK2, SIK3). This agent has the potential to overcome chemoresistance based on its mechanism of action (MOA) and synergistic effects with standard of care including paclitaxel, carboplatin, PARP inhibitors, and immune checkpoint inhibitors (ICIs). SIK2 is overexpressed in 30% of ovarian cancer specimens suggesting a multifunctional role of SIK2/3 in tumorigenesis. SIK2 and SIK3 are known to play [an] oncogenic role in other tumor types, including prostate cancer, breast cancer, diffuse large B-cell lymphoma, and melanoma. Higher levels of expression of SIK2 have been shown to be significantly correlated with poor progression-free survival in patients with high-grade serous ovarian cancers. GRN-300 attenuated tumor growth & inhibition in several preclinical xenograft ovarian cancer models as a single agent and in combination with paclitaxel. The clinical activity of GRN-300 as a single agent and in combination with paclitaxel is currently being evaluated in a Phase 1a/1b Clinical Study in subjects with Recurrent Ovarian, Primary Peritoneal, and Fallopian Tube Cancers (ClinicalTrials.gov Identifier: NCT04711161). About Greenfire Bio Greenfire Bio, led by a team of experienced biopharma executives, is building a diversified portfolio of oncology products through in-licensing, acquisition, and partnering, and is advancing them through clinical proof of concept. About Green3Bio Green3Bio is a subsidiary of Greenfire Bio. Green3Bio is developing GRN300 through clinical trials with the expertise of Greenfire Bio team members. The currently ongoing clinical trial (ClinicalTrials.gov Identifier: NCT04711161) is sponsored by Green3Bio. 1 J Clin Invest. 2022;132(11):e146471 2 3 CONTACT: Ajit Gill, President and CEO of Greenfire Bio at [email protected]. Website: greenfirebio.com LinkedIn: Facebook: #GreenfireBio, #cancer, #ovariancancer SOURCE Green3Bio