MCL1 抑制劑的全球市場：臨床試驗和商業化機會（2023 年）
Global MCL1 Inhibitor Drug Clinical Trials & Commercialization Opportunity Insights 2023
MCL-1 已被確定為多種癌症（主要是造血系統惡性腫瘤）發病機制中的核心蛋白。MCL-1 是一種動態且獨特的蛋白質，參與多種細胞功能，包括細胞週期進程、代謝和分化。然而，BCL-2 作為防止細胞凋亡的促生存成員的作用已被強調為有希望的癌症治療標靶。此外，MCL-1過度表現也透過各種訊號機制促進實體腫瘤和血液惡性腫瘤中對各種化療藥物的抗藥性。因此，MCL-1因其在促進細胞存活和治療抗藥性方面的重要作用而成為一個有前途的治療靶點，研究人員目前正在致力於尋找抑制MCL-1的策略，並且正在發揮作用。
與其他蛋白相比，標靶抑制MCL-1具有更多優勢。MCL-1 在許多癌症中過度表達，包括乳癌和肺癌，這兩種癌症的發生率和死亡率最高。MCL-1抑制癌細胞的凋亡過程並促進存活，導致腫瘤負荷增加。在臨床前研究中，MCL-1 的抑制被證明會誘導細胞死亡。此外，它還提高了與 MCL-1 抑制劑合併使用的其他抗癌藥物的療效。
此外，MCL-1 與目前治療產生抗藥性有關。特別是在血液癌症中，治療抗藥性在癌症患者中很常見，這對治療結果和患者存活提出了挑戰。MCL-1 的過度表現在其中發揮了作用，因為它抵消了誘導細胞凋亡的藥物的作用。標靶 MCL-1 可以克服這種抗藥性並提高用於治療造血系統癌症的化療的有效性。此外，透過將MCL-1抑制劑與其他標靶治療藥物或抗癌藥物合併使用，可望對癌細胞產生協同作用，促進細胞死亡，改善治療效果。
許多有前景的候選化合物的臨床前和臨床測試已經顯示出有希望的結果。S63845是第一批進入臨床前試驗的候選藥物之一，迄今已在多種實體癌症和造血系統癌症中進行了評估，顯示出有希望的結果。Servier和Novartis共同開發了S64315/MIK665，這是S63845的臨床試驗版本。如前所述，MCL-1 抑制劑是理想的組合藥物。因此，S64315 也正在與化療藥物氮胞甘和研究中的 BCL-2 抑制劑 VOB560 聯合用於造血系統癌症患者進行評估。
關於MCL-1抑制劑在癌症治療的應用，除了S63845外，許多在研候選化合物的臨床前試驗均取得了良好的結果，令人信服。此外，MCL-1有潛力用作各種惡性腫瘤的治療靶點，這些候選藥物在實體瘤中的部署結果證明了這一點。儘管MCL-1抑制劑的研發仍是一個新興領域，但Amgen、Novartis、AstraZeneca等知名製藥公司也正在投資開發這些候選化合物，展現了MCL-1抑制劑的潛力和潛力。這證實了未來幾年意想不到的市場成長。MCL-1 抑制劑仍存在需要解決的缺點，以實現 MCL-1 抑制劑市場的成長潛力。
“Global MCL1 Inhibitor Drug Clinical Trials & Commercialization Opportunity Insights 2023” Report Highlights:
MCL-1 has been identified as a central protein in the pathogenesis of several cancers, majorly hematopoietic malignancies. It is a dynamic and unique protein, which is involved in a variety of cellular functions, including cell cycle progression, metabolism, and differentiation among others. However, its role as a pro-survival member of the BCL-2 that prevents apoptosis is what has brought it into the limelight as a promising therapeutic target for cancer. In addition, overexpression of MCL-1 also promoted drug resistance of both solid tumors and hematological malignancies to various chemotherapeutic agents through different signaling mechanisms. Therefore, due its key role in promoting cell survival and the resistance to treatment, MCL-1 has emerged as a promising therapeutic target, and researchers are now working to find strategies to inhibit MCL-1.
Compared to other proteins, targeted inhibition of the MCL-1 is has more advantages. The protein is overexpressed in a number of cancers including breast and lung cancers, two cancers having the highest incidence and mortality rates. MCL-1 can prevent the process of apoptosis in cancer cells and promote survival, leading to increase in tumor mass. In preclinical trials, inhibition of the MCL-1 was shown to induce cell death. Additionally, it also increased the efficacy of other anticancer drugs administered in combination with the MCL-1 inhibitor.
Further, MCL-1 is also indicated in the development of resistance to current treatments. Especially in blood cancers, resistance to treatment is a common event occurring in cancer patients, and is something that has been challenging the treatment outcomes and survival of patients. Overexpression of MCL-1 plays a role in this as its upregulation can counteract the effects of drugs that induce apoptosis otherwise. Targeting the MCL-1 can overcome this resistance and enhance the effectiveness of chemotherapies used in treating hematopoietic cancers. Adding on to this, the combination of MCL-1 inhibitors with other targeted therapies and anticancer drugs can have a synergic effect on cancer cells, leading to enhanced cell death and improved treatment outcomes.
Research has also found that while normal cells rely on several survival mechanisms, most cancer cells become highly dependent on MCL-1 for their survival. Therefore, it is hypothesized that targeting the MCL-1 will be a highly targeted strategy specific towards cancer cells, and it will leave non-cancer cells unharmed. To some extent, results from clinical and preclinical trials conducted by researchers and drug developers have been able to justify this. Though there remain some limitations such as the emergence of unforeseen adverse effects such as cardiac problems, the potential of MCL-1 as a therapeutic target cannot be denied, and is an avenue that needs to be explored more with potential candidates.
Results from preclinical and clinical trials for many promising candidates have returned encouraging outcomes. S63845 was among the first candidates to enter preclinical trials, and till date it has been assessed in a number of solid and hematopoietic cancers, and has shown promising results. Servier and Novartis jointly developed S64315/MIK665, the clinical-trial version of S63845. As mentioned above, MCL-1 inhibitors can act as ideal combinatorial agents. Therefore, S64315 too is being assessed in combination with azacitidine, a chemotherapeutic drug, and VOB560, an investigational BCL-2 inhibitor, in patients with hematopoietic cancers.
A compelling case has been made for the use of MCL-1 inhibitors in the treatment of cancer by the positive preclinical trial results of numerous other investigational candidates besides S63845. MCL-1 also has the potential to be used as a therapeutic target for a variety of malignancies, as evidenced by the outcomes of the expansion of these candidates to solid tumors. Research and development of MCL-1 inhibitors is still an emerging field, however, prominent pharmaceutical companies like Amgen, Novartis, and AstraZeneca have also invested in the development of these candidates, which vouches for the future potential of MCL-1 inhibitors and the unanticipated market growth in the coming years. There still remain certain drawbacks associated with MCL-1 inhibitors that need to be addressed to realize the prospective growth potential of the MCL-1 inhibitors market.