NCOR2

本研究发现WK369是一种新型的BCL6小分子抑制剂，在体外和体内均能显著抑制OV的生长和迁移，且无毒性，延长荷瘤小鼠的生存期。 卵巢癌(OV)被认为是最致命的女性生殖器恶性肿瘤之一，在妇科癌症中发病率和死亡率最高。当卵巢癌诊断为Ⅰ期或Ⅱ期时，5年生存率可达89%和71%。然而，由于早期无症状，约70%的卵巢癌患者在诊断时存在远处转移性疾病(III期或IV期)。这些患者的5年生存率低于25%。导致OV患者生存差的主要问题是转移和化疗耐药性。因此，开发创新的治疗方法来预防获得性化疗耐药或卵巢癌转移是至关重要的。 图片来源：https://pubmed.ncbi.nlm.nih.gov/38169532/ 近日，来自华东师范大学的研究者们在Int. J. Biol. Sci.杂志上发表了题为“Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer”的文章，该研究表明靶向BCL6可能是治疗卵巢癌的有效途径，WK369具有作为卵巢癌候选治疗剂的潜力。 卵巢癌是妇科肿瘤中致死率最高的肿瘤之一。目前卵巢癌的5年生存率<35%。因此，需要更多新颖的替代策略和药物来治疗卵巢癌。转录因子b细胞淋巴瘤6 (BCL6)在卵巢癌治疗中与不良预后和顺铂耐药密切相关。因此，BCL6可能是卵巢癌的一个有吸引力的治疗靶点。然而，靶向BCL6在卵巢癌中的作用尚不明确。 在此，研究者开发了一种新的BCL6小分子抑制剂WK369，它具有良好的抗卵巢癌生物活性，可诱导细胞周期阻滞并导致细胞凋亡。WK369在体外和体内均能有效抑制卵巢癌的生长和转移，无明显毒性。同时，WK369能延长卵巢癌小鼠的生存期。值得注意的是，WK369对顺铂耐药卵巢癌细胞系也有明显的抗肿瘤作用。 机制研究表明，WK369可直接结合BCL6- btb结构域，阻断BCL6与SMRT的相互作用，导致p53、ATR和CDKN1A的再激活。BCL6-AKT、BCL6-MEK/ERK串扰被抑制。 WK369被鉴定为BCL6-BTB抑制剂 图片来源：https://pubmed.ncbi.nlm.nih.gov/38169532/ 综上所述，本研究发现WK369是一种新型的BCL6小分子抑制剂，在体外和体内均能显著抑制OV的生长和迁移，且无毒性，延长荷瘤小鼠的生存期。WK369可抑制OV获得性顺铂耐药细胞，增强OV顺铂耐药细胞株对顺铂的敏感性。因此，WK369可能为卵巢癌与顺铂的联合治疗提供新的策略。（生物谷 Bioon.com） 参考文献 Min Wu et al. Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer. Int J Biol Sci. 2024 Jan 1;20(2):486-501. doi: 10.7150/ijbs.86303.

意外怀孕作为一个重要的公共卫生问题，仅在美国每年就造成数十亿美元的损失，因此科学合理避孕具有重要的社会经济价值和健康效益。然而，目前上市的避孕药物用于男性依然较少。图1. 文章标题近日，索尔克生物研究所埃文斯博士团队在国际知名期刊PNAS发表了题为“Targeting nuclear receptor corepressors for reversible male contraception”的研究性文章，文章发现通过长期、低剂量口服组蛋白脱乙酰酶抑制剂来抑制类视黄醇和甲状腺激素受体SMRT复合物的作用，可逆地阻止精子发生,进而达到男性避孕效果，而停药后并不影响男性正常生殖功能，展示了其一种具有潜力的低副作用长效男性避孕药的开发潜力。那么，为什么男性避孕药这么少？长期以来，男性避孕药的缺乏可能是由于精子发生的复杂性，在男性体内，视黄酸受体（RAR）可以调节睾丸中精原干细胞（SSC）的一系列自我更新和分化程序，RA的精确水平以及由此产生的 RAR 激活/抑制对于正常精子发生至关重要。一款理想的男性避孕药物必须在抑制睾丸精子发生的同时，还必须保留精原干细胞，并且不会永久损害男性生殖系统。因此，开发新型可用于男性避孕药一直具有挑战性。SMRT复合物在精子发生过程中的作用在这项研究中， 研究人员主要利用了SMRTmRID转基因小鼠，与杂合子对照组的雄性小鼠相比，雄性纯合子 SMRTmRID突变小鼠是不育的，并在1月龄左右出现明显的进行性睾丸退化和原发性生精衰竭。虽然性成熟SMRTmRID小鼠表现出正常的发情行为，但在附睾头中几乎没有检查到成熟的精子。后续，研究人员使用该小鼠模型进行了深入探究。 图2. SMRTmRID小鼠睾丸变性和独立于维生素 A 的精子发生由于视黄醇和甲状腺激素受体沉默介质 (SMRT)在整个睾丸细胞群中普遍表达，并在支持细胞和生殖细胞中表达最高。因此，研究人员进一步分析了维生素A和RAR 信号传导在MRTmRID小鼠中的作用。结果表明MRTmRID小鼠生殖细胞的逐渐丧失可能是SSC分化失控的结果，而SSC自我更新和分化之间的平衡对于可持续的精子发生至关重要。此外，在这个过程中，精确控制 RAR 激活/抑制的时间对于精子的发生同样重要。靶向SMRT复合物避孕的机制探究 图3. MRTmRID小鼠支持细胞中 RAR 靶基因的去抑制和生精周期的异步进展为了进一步探究RAR在MRTmRID小鼠体内的生物学机制，研究人员通过全基因组转录组分析确定了对照细胞和 MRTmRID小鼠体内生殖干(GS) 细胞中 RAR 配体、全反式维甲酸(ATRA)诱导的转录变化，结果再次证明了RA在介导SSC分化的重要作用。此外，从圆形精子细胞发育成细长精子细胞需要精子细胞特异性鱼精蛋白在时间和空间上同步替换组蛋白，但是研究人员发现MRTmRID小鼠生精进展的显著异步性，而这种异步性是由RA 诱导的生精程序丧失，而不是简单的 RAR 靶基因调控的丧失。同时，研究人员还发现MRTmRID小鼠生精小管周期性基因表达缺失以及支持细胞与圆形精子细胞相互作用存在缺陷，导致圆形精子细胞过早释放到附睾中从而造成精子发生受损。 图4. MRTmRID小鼠Sertoli 细胞中分化生殖细胞的丧失和细胞骨架网络缺陷研究人员还发现虽然MRTmRID小鼠青春期前第一轮精子发生相对正常 ，但波形蛋白和酪氨酸微管蛋白的免疫荧光结果分别显示，生精小管中支持核和微管极化的异常，但是其血睾屏障（BTB）并未受到损害。靶向SMRT复合物的避孕效果评价有研究表明，辅阻遏物复合物的组蛋白脱乙酰酶 (HDAC)成分可以介导 SMRT 的转录活性抑制，这使得研究人员推测通过HDAC 的药理学抑制可以对 MRTmRID介导的表观遗传变化进行表型复制，以解除对 RAR 靶基因的抑制。因此，研究人员在小鼠上使用HDAC抑制剂MS-275对小鼠体内的精子发生过程进行了分析。结果表明HDAC抑制剂破坏了小鼠的精子发生，但是没有降低血清睾酮水平和SSC的存在。并且，在停药 60 天后，小鼠恢复生育能力，产下健康无畸形幼崽。这些结果都表明长期口服 MS-275 会暂时阻断男性生育能力，但不会永久影响生殖能力或精子基因组完整性。 图5. 组蛋白脱乙酰酶抑制可阻止小鼠精子发生。总结看完上面专业性的分析，下面我们再用通俗的语言总结下这篇文章。男性避孕药的开发难点在于男性精子发生过程中包含多级步骤的复杂性，而研究人员在这项研究中发现解除SMRT复合物信号传导的抑制可以在不影响正常生殖功能的情况下达到避孕效果，这为以后开发新型的男性避孕药打开了新思路。参考文献：Hong, S. H. (2024). Targeting nuclear receptor corepressors for reversible male contraception. Proceedings of the National Academy of Sciences of the United States of America, 121(9), e2320129121. https://doi.org/10.1073/pnas.2320129121撰文 | 安小猪编辑 | lcc部分文字来源于网络，本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！精彩推荐：1、「16+8 还不够」Nature子刊：超十万人队列研究显示，早餐早于8 AM+晚餐早于8 PM更能减少肥胖、糖尿病风险2、「不止是配角」上海交大研究团队经6万中国男性随访12年调查发现：这种超级食物具有保肝防癌奇效3、科学设闹钟，助力无痛早八！最新研究表明：闹钟响后再贪睡30分钟可缓解睡眠惯性并改善认知功能4、最有效的减肥方式竟是「抖腿」！Cell子刊：每天“抖腿”270分钟，消耗能量翻一番！5、「这个基因决定了你的减肥效果」Nat. Commun最新研究：抑癌基因 p53 信号传导调节小鼠和人类间歇性禁食的效果

The drug works by targeting a component of the process that turns sperm stem cells into sperm. A drug with a past life as a potential anti-cancer agent might someday have a new job as "the pill" for men, new data in mice suggest.  In a journal article published Feb. 20 in Proceedings of the National Academy of Sciences, researchers at the Salk Institute explained how they discovered that an oral HDAC inhibitor called entinostat acts like an “off-on” switch for sperm creation that keeps male mice from reproducing without any effect on their libido. Within 60 to 90 days of stopping the pill, the mice were able to impregnate female animals again without any harm to the resulting offspring.  Effective male contraceptives are a long time coming, senior author Ronald Evans, Ph.D., told Fierce Biotech Research in an interview. Researchers have been trying for decades to develop a noninvasive, reversible, easily accessible drug candidate that is as effective as the birth control pill is for women, with no success so far.   “Our game-changing or transformative results are that it’s now possible to have a male equivalent of the pill that’s able to give men control as well, without having to rely on condoms,” Evans said. (Of course, this wouldn’t eliminate the need for condoms—they’re still necessary to protect against some types of sexually transmitted disease.) Sperm production is a complex process with many components, a limiting factor in coming up with drugs to block it. Hormonal candidates, such as the drug DMAU, have mainly focused on blocking testosterone—a route that varies in effectiveness depending on the patient population and can come with side effects. A non-hormonal injectable drug called RISUG is making its way through clinical trials in India, and a version called Vasalgel is in development in the U.S. However, both of these require either an injection or an in-office procedure.  One non-hormonal mechanism that scientists have long considered is blocking receptors for retinoic acid, a form of vitamin A that is critical to the process whereby sperm stem cells differentiate into fully functional sperm. But while this does stop sperm production in mice and rats, it comes at a cost: Retinoic acid is needed for a wide range of processes throughout the body, so inhibiting its activity systemically can lead to serious side effects, Evans explained. “You can kind of get it to work the way you want, but it’s not specific enough to be a useful way to address the challenge of controlling spermatogenesis,” he said. Researchers have largely abandoned the effort in favor of other approaches.  But in the new study, Evans’ lab—which was the first to clone the receptor for retinoic acid—learned that there’s another way to go about blocking its role in sperm production without systemic effects. While studying a gene regulatory factor called SMRT, one of the researchers in his lab pointed out that it was part of a complex of proteins that were involved in regulating retinoic acid receptors in sperm creation.  “He suggested that maybe we should actually not target the retinoic acid receptor itself, but target SMRT,” Evans recalled. Not only would doing so be easier than targeting the receptor directly, but it would also be safer because the target’s systemic effects are more limited, he added.  This led the team to see if blocking SMRT with entinostat, which Evans co-developed under his former company Syndax, would be a solution, as SMRT’s function is controlled by the same components that are interrupted by HDAC inhibitors. They gave male mice one of three different doses of the drug once a day for 60 days, then tested their ability to mate. They also tested whether taking mice off the drug would restore sperm production—and whether it would affect the health of their offspring.  To their surprise, the approach was a success.  “[The researcher] came back and said, ‘It really works.’ I said, ‘What do you mean it really works?’” Evans recalled. “He said, ‘It’s a total contraceptive. The mice’s libido is totally normal. And if you take it away, [their ability to reproduce] comes back.’” None of the mice that were on the drug sired offspring during the treatment period, compared to litters of around 10 pups each from control males. Sixty days after stopping the treatment, mice in the experimental groups were able to impregnate females again to the same degree as controls. All of the pups were born healthy.  During the treatment period, the researchers noticed that the animals’ testis size was “dose-dependently reduced” as their sperm production capacity fell. This was mostly recovered after 60 days off the drug, figures in the article showed. There were no other discernible side effects, such as weight loss that would indicate a change in testosterone levels, the researchers wrote in their paper. “As a proof of principle, our findings indicate that chronic, oral administration of MS-275 transiently blocks male fertility without permanently affecting reproductive capacity or the genomic integrity of sperm,” they wrote. Evans now hopes to test entinostat as a male contraceptive in larger animals and eventually in humans. The drug already has FDA breakthrough status for advanced breast cancer and has been studied in clinical trials for pancreatic cancer, brain cancer, melanoma and other cancers, so safety in humans has already been established, he said.  Given the results, Evans’ team has no plans to look at whether other HDAC inhibitors have birth control potential as well, he said, though they might look at other medical uses for entinostat. But for now, its use as a male contraceptive “is at the top of the list,” he said.  “That’s where we want to focus and see if there is a company that wants to actually develop this. Or do we have to start our own?” Evans, a serial biotech entrepreneur, said. “That’s kind of fun to think about.”