Development of novel functional inhibitor for mitotic kinesin Eg5 as a target cancer therapy

• Material Type: 博士論文
• Title: Development of novel functional inhibitor for mitotic kinesin Eg5 as a target cancer therapy
• Author/Editor: Islam, Md Alrazi; Md Alrazi, Islam
• Author Heading: Islam, Md Alrazi; Md Alrazi, Islam
• Publication Date: 2022-03-18
• Publication Date (W3CDTF): 2022-03-18
• Degree grantor/type: 創価大学
• Date Granted: 2022-03-18
• Date Granted (W3CDTF): 2022-03-18
• Dissertation Number: 甲第189号
• Degree Type: 博士（工学）
• Text Language Code: eng
• Subject Heading: Kinesin; Kinesin Eg5; Mitosis cell division; Loop 5, Eg5 inhibitors; Photochromic compound; Isomerization
• Target Audience: 一般
• Note (General): Kinesin is a motor protein that plays an important role in animal and plant cells. It hydrolyzes ATP and moves along microtubules. It means that motor proteins are extremely fine machines that can efficiently convert the chemical energy produced by ATP hydrolysis into mechanical energy. In fact, martin et.al. (2007) propose that motor proteins could be applied to various fields as ‘’ nanomachines’’. Eg5 belongs to the motor protein. It involves in the transport of the endoplasmic reticulum and organelles, and the transport of neurotransmitters from nerve bodies to synaptic terminals in nerve axons. It also plays a crucial role in mitotic cell division for the formation of the bipolar spindle in the eukaryotic cell division. Therefore, it has been suggested that mitotic kinesin Eg5 is considered a potential target for cancer therapy.The various functions of Eg5 are proposed in equivalent polymorphisms in the key kinesin structural elements. One of the functional elements of Eg5 is referred to as Loop 5(L5). Especially, L5 of Eg5 has a very long structure unlike other kinesins and acts as the target for binding of small molecular inhibitors. For the application of Eg5 motor proteins as nanomachines, it is essential to artificially control the mechanical structure that changes with external stimulation. Some of the results have continued for the development of inhibitors for Eg5. Interestingly, several small-molecule compounds (such as monastrol, S-Triyl-L-Cysteine (STLC), Ispinesib, and so on) have been shown the Eg5 inhibitory activity. They are binding to the same druggable Eg5 allosteric pocket, which is composed of Loop L5, α2, and α3. However, they showed structural diversity and control the activity of Eg5 unidirectionally or irreversibly. They could not be applied as nanodevice to control the functional activity of Eg5 reversibly. Therefore, switching is required to control Eg5 activity reversibly not only in general but also in functional.To do that, I focused on chromism. Chromism refers to a phenomenon in which the optical properties (color, fluorescence, etc.) of a substance are reversibly changed by external stimulation such as heat, pH, light, and so on. A substance that exhibits chromism is called a chromic substance (or chromic material). First, it is suggested that heat could work as a switching like as- high, low, and room temperature. However, in this study, I have used a protein that is highly sensitive to high temperatures. Therefore, thermal is not an appropriate technique for switching. Subsequently, I focused on the development of switching with different pH like as- acidic, alkaline, and neutral pH. Unfortunately, both the acidic and alkaline pH is harmful to the general structure of the protein. Hence, pH could not be applicable for working as a switching. Finally, I focused on light for the establishment of switching. It has been well known that photochromic compounds show light sensitivity. Photochromic compounds are those compounds that show their structural and functional changes depends upon the light irritation. There are two types of mechanisms observed for returning to their original states. A mechanism that returns by irradiating light with a different wavelength, it’s called P-type such as diarylethene and fulgide. Another one, a mechanism that returns by heat, it’s called T-type such as spiropyran, azobenzene, and stilbenes.Interestingly, some of the photochromic compounds showed structural similarity with well-known potent Eg5 inhibitors such as spiropyran. Sadakane, et.al, designed and synthesized a novel photochromic Eg5 inhibitor composed of double photochromic compounds, spiropyran, and azobenzene. The inhibitor displayed two isomerization states and controlled Eg5 activity. Generally, one photochromic compound shows two isomerization states. Theoretically, coupling of two different photochromic compounds could show multiple isomerization states which would be effective to establish photo switching precisely. In our laboratory, photo switching has been using as a well-established technique to control protein activity for the last two decades. I focused on obtaining novel inhibitors from synthetic or natural sources and then react with photochromic compounds. The most changeling task is designing of photochromic inhibitor for controlling Eg5 activity in multiple stages. In this study, I demonstrated to develop a novel Eg5 inhibitor which has two parts, such as- one is regulatory part, and another is inhibitory part to control Eg5 function in multiple states like strongly, weakly and mediumly.Firstly, to achieve that, I designed and combined two different photochromic compounds such as spiropyran and azobenzene to make regulatory part and it displayed inhibitory effect in multiple states. Interestingly, merely the regulatory part exhibited control action on Eg5. Secondly, I focused on to discover a new and potent Eg5 inhibitor from natural sources for the inhibitory part. Eg5 inhibitor from natural sources that I utilized in this research is Kolaroflavon and which exhibited effective control action for Eg5. In the future, that could be formed multiple states with photochromic compounds (e.g- STLC- Azobenzene derivatives, Ishikawa et.al). The aim of the study, the formation of multiple states have the clinical significance for the treatment of cancer patients. The inhibitory activity of drugs could be controlled precisely, in terms of high dosage, low dosage, or medium dosage, considering the patient’s condition.
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• Date Accepted (W3CDTF): 2023-10-11T15:41:03+09:00
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• Periodical Title (URI): http://hdl.handle.net/10911/00040740; https://soka.repo.nii.ac.jp/records/40747
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