同行致远 | 靶向“不可成药”靶点！创新疗法正在重新定义癌症治疗边界

Core Insights - The focus of cancer drug development is shifting towards targeting "undruggable" targets, moving from traditional optimization of mature targets to innovative strategies that aim to overcome long-standing challenges in drug development [1][16][29] Target: MYC - MYC has been considered a classic "undruggable" target due to its dynamic protein structure and lack of stable binding pockets, making traditional small molecules ineffective [1][16] - The mini-protein therapy OMO-103 has shown promising early activity signals in human studies, with manageable safety profiles and no dose-limiting toxicities observed, particularly in advanced solid tumors [2][17] - A targeted degradation approach using VHL E3 ligase recruitment has demonstrated the ability to dose-dependently clear endogenous MYC protein, showing biological activity in breast and prostate cancer models [2][17] Target: KRAS - KRAS is recognized as one of the most representative "undruggable" targets in oncology, with drug development hindered by its unique molecular biology [3][18] - The KRAS G12C inhibitors sotorasib and adagrasib have received FDA approval, marking a shift towards broader precision interventions [3][18] - The RAS(ON) tri-complex inhibitor zoldonrasib has shown a 61% objective response rate in previously treated non-small cell lung cancer patients, indicating effective pharmacological control over the KRAS G12D mutation [3][18][20] Target: MTAP - MTAP deficiency presents a unique challenge, as it is not a traditional oncogenic driver but is prevalent in various tumors, leading to a lack of clear drug development pathways [6][21] - The PRMT5 inhibitor AMG193 has shown selective inhibition of tumor cells with MTAP deficiency, demonstrating initial anti-tumor activity in late-stage solid tumor patients [6][21][22] - Other candidates like MRTX1719 and TNG462 are in early clinical studies to further validate the synthetic lethality strategy associated with MTAP deficiency [6][22] Target: TP53 - TP53 mutations are widespread in human cancers, complicating traditional inhibitor strategies due to the loss of tumor suppressor function [7][23] - MDM2 inhibitors aim to restore p53 function by relieving its inhibition, with early studies confirming the activation of the p53 pathway and tumor growth suppression [7][23][25] - Small molecule correction strategies targeting mutant TP53 have shown preliminary clinical response signals, indicating potential for restoring p53 function [7][25] Target: WNT/β-catenin Pathway - The WNT/β-catenin pathway is essential for physiological processes but poses safety challenges in therapeutic development due to its role in embryonic development and tissue homeostasis [8][11][26] - The PORCN inhibitor zamaporvint has shown clinical benefit in combination with PD-1 inhibitors in specific colorectal cancer patients, achieving a disease control rate of 57.1% [8][11][26] - Downstream regulatory strategies, such as β-catenin–TBL1 complex inhibitors, are being explored for their potential to selectively modulate tumor activity while maintaining normal physiological functions [8][11][27]