药物化学家如何创造新的武器来对抗自身免疫性疾病

For Kristine Frank, the best part of her job is making a chemical compound that the world has never seen before.

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She’s a senior principal research scientist at AbbVie, where she makes new molecules with the goal of helping address unmet needs for people living with autoimmune diseases. It just so happens that her father, who lives with rheumatoid arthritis, is one of those people.

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Kristine弗兰克,她的工作是最好的部分做一个化合物,世界从未见过的。

她是个高级AbbVie首席研究科学家,她使新分子的目标是帮助解决自身免疫性疾病患者的未满足的需求。碰巧她的父亲,谁生活在风湿性关节炎,是这些人之一。

“Our team’s job is to design and synthesize small molecules that no one has ever made before,” Frank said. “It’s such an exciting challenge, but to know my work could also help people like my father is an incredible feeling and motivator.” It’s a challenge that can take more than 10 years to develop, on average, and requires dedicated and creative problem solvers like Frank.

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In the face of such overwhelming odds, how can researchers tip the scales in their favor? At AbbVie, the journey to a new medicine uses strong science as a roadmap. Researchers aren’t simply screening vast libraries of compounds for one that may work. They are applying lessons learned from previous discoveries and blazing the trail to new therapies using data-driven research and cutting-edge chemistry.

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“我们的团队的工作是设计和合成小分子,之前没有人做过,”弗兰克说。“这是这样一个令人兴奋的挑战,但也知道我的工作可以帮助人们喜欢我的父亲是一个令人难以置信的感觉和动力。“这是一个挑战,可以超过10年的发展,平均,需要专用的和创造性的解决问题就像弗兰克。

面对这样的压倒性优势,研究人员在他们的优势如何?在AbbVie,旅行到一个新的医学使用强大的科学作为一个路线图。研究者并不是简单地筛选大量的化合物库,可能工作。他们从先前的发现和应用经验教训指明了道路使用数据驱动的研究和先进的化学新疗法。

Take rheumatoid arthritis (RA), for example, which is the most common form of autoimmune arthritis. RA is a chronic, systemic inflammatory disease that occurs when the body’s overactive immune cells mistakenly attack the joints, leading to painful and swollen joints, stiffness, fatigue, fever and loss of appetite.1 Yet, despite multiple treatment options that work in multiple different ways, most people living with RA have not achieved either low disease activity or clinical remission. Those are the primary goals of treatment, as defined by American College of Rheumatology guidelines.2,3

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One reason that immune-mediated diseases like RA are tough to treat is that they involve complex signaling pathways. How does a medicinal chemist know where to focus their efforts for creating new a medicine?

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“Believing in your science is key,” said Carolyn Cuff, Senior Director, Translational Immunology Department at the AbbVie Bioresearch Center. “Developing a specific strategy and hypothesis about why a new compound is different from other medicines in the class must be anchored in data, and then you have to trust that data to guide you forward.”

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类风湿性关节炎(RA),例如,这是最常见的自身免疫性关节炎。类风湿性关节炎是一种慢性全身性炎性疾病,发生在身体的过度活化的免疫细胞错误地攻击关节,导致疼痛和关节肿胀、刚度、疲劳、发烧、食欲不振。1然而,尽管多个治疗方案在多个不同的方式工作,大多数人生活在RA疾病活动不是实现低或临床缓解。这是治疗的主要目标,所定义的美国风湿病学院guidelines.2, 3

免疫介导性疾病如风湿性关节炎的一个原因是很难治疗涉及复杂的信号通路。药用化学家知道如何集中他们的努力为创造新的药吗?

说:“相信你的科学是关键,”卡manbet体育网址罗琳袖口,高级主管,平移免疫学系主任AbbVie生物学研究中心。“发展中一个特定的策略和假设关于为什么一个新的化合物是不同于其他药物类必须被锚定的数据,然后你必须相信这些数据来指导你前进。”

Take rheumatoid arthritis (RA), for example, which is the most common form of autoimmune arthritis. RA is a chronic, systemic inflammatory disease that occurs when the body’s overactive immune cells mistakenly attack the joints, leading to painful and swollen joints, stiffness, fatigue, fever and loss of appetite.1 Yet, despite multiple treatment options that work in multiple different ways, most people living with RA have not achieved either low disease activity or clinical remission. Those are the primary goals of treatment, as defined by American College of Rheumatology guidelines.2,3

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One reason that immune-mediated diseases like RA are tough to treat is that they involve complex signaling pathways. How does a medicinal chemist know where to focus their efforts for creating new a medicine?

\r\n

“Believing in your science is key,” said Carolyn Cuff, Senior Director, Translational Immunology Department at the AbbVie Bioresearch Center. “Developing a specific strategy and hypothesis about why a new compound is different from other medicines in the class must be anchored in data, and then you have to trust that data to guide you forward.”

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类风湿性关节炎(RA),例如,这是最常见的自身免疫性关节炎。类风湿性关节炎是一种慢性全身性炎性疾病,发生在身体的过度活化的免疫细胞错误地攻击关节,导致疼痛和关节肿胀、刚度、疲劳、发烧、食欲不振。1然而,尽管多个治疗方案在多个不同的方式工作,大多数人生活在RA疾病活动不是实现低或临床缓解。这是治疗的主要目标,所定义的美国风湿病学院guidelines.2, 3

免疫介导性疾病如风湿性关节炎的一个原因是很难治疗涉及复杂的信号通路。药用化学家知道如何集中他们的努力为创造新的药吗?

说:“相信你的科学是关键,”卡manbet体育网址罗琳袖口,高级主管,平移免疫学系主任AbbVie生物学研究中心。“发展中一个特定的策略和假设关于为什么一个新的化合物是不同于其他药物类必须被锚定的数据,然后你必须相信这些数据来指导你前进。”

Many immune-mediated diseases are already being treated using different compounds, but changes in the chemical structure of these compounds could lead to better treatments. That’s why the power of medicinal chemistry can really be a gamechanger. But that can mean that we need to build something that had never been built before.

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Making a new compound and testing it can be really tough, said Michael Friedman, a principal scientist at AbbVie.

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许多免疫介导性疾病已经治疗使用不同的化合物,但这些化合物的化学结构的变化可能会导致更好的治疗方法。这就是为什么药物化学的力量真的可以成为一个改变游戏规则。但这可能意味着我们需要构建一些以前从未建成。

做一个新的化合物和测试它可以真的很艰难,在AbbVie首席科学家迈克尔·弗里德曼说。

“You encounter a lot of failures,” Friedman said. “You make a compound, the compound is not potent. You make another compound, the compound is not selective. That can go on for a while unless you’re working off a strong hypothesis.”

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Medicinal chemists, like Frank and Friedman, often have to design and make thousands of compounds over the course of a project. Each compound is tested and evaluated for positive and negative features, and those learnings feed into the next round of design and synthesis. The process is repeated until they find the one compound that works.

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“Once you figure out how to make a new compound, things really start to unfold and can become really exciting,” Friedman said. “Nothing excites you more than success.”

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The success of this strategic approach – called rational design and synthesis – at AbbVie has helped scientists more efficiently investigate potential small molecules that may have therapeutic benefit.

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“Even if a compound is incredibly hard to make, that doesn’t mean that you shouldn’t make it. Once we’ve critically evaluated compounds in silico and convinced ourselves that a compound needs to be made, then this compound will be made because there’s almost nothing that we cannot make,” Friedman said. “That’s our spirit here at AbbVie.”

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“你遇到很多失败,”弗里德曼说。“你复合,复合不是有效的。你让另一个化合物,化合物没有选择性。可以继续工作一段时间,除非你强烈的假设。”

药物化学家,像弗兰克和弗里德曼,往往设计,使成千上万的化合物的一个项目。每个化合物是积极的和消极的特性的测试和评估,这些知识融入到下一轮的设计和合成。重复这个过程,直到他们找到工作的一种化合物。

“一旦你找出如何使一个新化合物,事情真的开始展开,可以成为真的令人兴奋,”弗里德曼说。“没有什么比取得成功更让你兴奋。”

这一战略的成功方法,称为理性的设计和合成,AbbVie帮助科学家更有效地调查潜在的小分子,可能治疗中获益。

“即使一个复合极其困难,这并不意味着你不应该让它。一旦我们批判性评估化合物在硅片和说服自己,需要一种化合物,这种化合物会因为几乎没有,我们不能做,”弗里德曼说。“这是我们的精神在AbbVie。”