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一种核酸独立的,泛RAS向的DARPin以多式方式引起抗瘤活性

Jonas N Kapp¹, Wouter P R Verdurmen¹, Jonas V Schaefer¹

¹Department of Biochemistry, University of Zurich, Switzerland.

Molecular oncology

|June 15, 2025

概括

一种新型的设计基林重复蛋白 (DARPin) 针对KRAS基蛋白,阻止其激活和下游信号传输. 这种核酸独立的方法有效地减少了癌细胞的增殖,并在临床前模型中诱导了瘤回归.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

克拉斯瘤蛋白是肺癌,胰腺癌和结直肠癌的关键驱动因素.
针对KRAS一直是具有挑战性的,对核酸状态特异性和RAS纳米集群的理解有限.
现有的针对KRAS的治疗方法正处于早期临床试验阶段.

研究的目的:

开发和描述一种新的泛RAS,核酸独立抑制剂.
调查针对RAS开关I/II区域对KRAS激活和下游信号的影响.
在临床前癌症模型中评估开发的抑制剂的治疗潜力.

主要方法:

开发一种针对RAS开关I/II区域的设计安基林重复蛋白 (DARPin).
对DARPin结合亲和力和核酸状态独立性的评估.
评估DARPin对SOS介导激活和效应因子相互作用的干扰.
对DARPin对KRAS纳米集群的影响分析.
在RAS-依赖细胞系中的增殖和结独立生长的体外评估.
在肠直肠外移植模型中对DARPin疗效的体内评估.

主要成果:

一种新的DARPin'784_F5'被开发出来,它对RAS具有较低的纳米分子亲和力,独立于GDP/GTP结合.
"784_F5"干扰了SOS介导的激活,RAS效应器相互作用和KRAS纳米集群.
DARPin有效地阻断了下游的信号传输,显著减少了癌症细胞系的增殖和固独立生长.
"784_F5"的表达导致结直肠外移植模型中的瘤回归.

结论:

开发的泛RAS,核酸独立的DARPin ("784_F5") 能够有效地抑制KRAS信号传递.
这种方法证明了通过向保存的RAS结构元素来治疗KRAS驱动癌症的潜力.
"784_F5"值得进一步研究和开发,作为一种新的癌症治疗方法.

关键词:

设计的安基林重复蛋白质拉斯拉斯拉斯拉斯拉斯拉斯拉斯拉斯拉斯癌症癌症癌症癌症癌症药物开发是药物的发展.在基因上,我们发现了基因上的差异.小型的GTP酶.

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