DUSP6

Promising exarafenib combination data in NRAS mutant melanoma; intend to select two doses in the fourth quarter of 2023 for further development Plan to file KIN-8741 c-MET inhibitor Investigational New Drug application and nominate a drug candidate for brain-penetrant CDK4 selective program in the fourth quarter of 2023 Completed exarafenib monotherapy dose expansion enrollment and cleared efficacious dose for KIN-3248, FGFR inhibitor; exploring strategic alternatives for both programs Paused KIN-7136 MEK inhibitor development and implementing a workforce restructuring, aligned with reprioritization plan Cash, cash equivalents and investments of $204.3 million as of June 30, 2023, anticipated to fund operations into at least the second quarter of 2026 SAN FRANCISCO and SAN DIEGO, Sept. 18, 2023 (GLOBE NEWSWIRE) -- Kinnate Biopharma Inc. (Nasdaq: KNTE) (“Kinnate” or “the Company”), a clinical-stage precision oncology company, today announced pipeline updates and a reprioritization plan, as well as a workforce restructuring, based on a strategic review of its business. The review encompassed various factors, including the Company's cash runway, near-term pipeline value creation prospects, the evolving regulatory landscape for targeted therapies, commercial potential, development strategy, and other relevant considerations. As a result, the Company is prioritizing the exarafenib combination, KIN-8741, and discovery efforts around its CDK4 selective program. Additionally, Kinnate will pause development of KIN-7136 and explore strategic alternatives for exarafenib monotherapy and KIN-3248, as part of the reprioritization plan. Concurrently, the Company will implement a workforce restructuring to align with its refined focus. Nima Farzan, chief executive officer of Kinnate Biopharma Inc., commented, “Today, we are taking hard but necessary steps to streamline our programs, team and operations in order to advance our research and deliver meaningful benefits to patients and shareholders alike. These decisions reflect the current financing environment, oncology regulatory landscape and development timelines. We believe that reprioritizing our programs is the most effective approach to unlock the full promise of our innovative therapies.” Farzan added, “The reprioritization plan unfortunately impacts our workforce. It is undoubtedly difficult to part with our valued and highly talented employees who have made substantial contributions to our company. I want to thank each one of them for their dedication to Kinnate and our mission.” Pipeline Updates and Reprioritization Plan Investigational Exarafenib Combined with Binimetinib: Pan-RAF plus MEK Inhibitor Dose exploration for the combination of exarafenib and binimetinib is currently underway in the KN-8701 clinical trial, with a primary focus on NRAS mutant melanoma. NRAS alterations are detected in approximately 20-25% of melanoma patients, and as of today, there are no approved targeted therapies available for this subgroup, highlighting a significant unmet medical need. As of September 11, 2023, the data cutoff, 44 patients with NRAS mutant melanoma and BRAF-altered solid tumors were enrolled across 6 exarafenib plus binimetinib combination dose cohorts, including 24 patients who continue on therapy. In the first 5 cohorts, among 20 efficacy-evaluable patients with NRAS mutant melanoma (including Q61 and non-Q61 mutations), 12 patients had radiographic tumor reductions. Among 16 efficacy-evaluable patients with NRAS mutant melanoma who had not received prior RAF, MEK, or ERK inhibitors, 6 achieved confirmed and unconfirmed partial responses (PRs), resulting in a 38% overall response rate (ORR), with 5 additional patients experiencing stable disease (SD) as their best response, yielding a 69% disease control rate (DCR). In a subgroup of 17 efficacy-evaluable patients with NRAS Q61 mutations, which represent up to 90% of all NRAS melanoma mutations, 7 achieved confirmed and unconfirmed PRs, leading to a 41% ORR, and 6 others had SD as their best response, resulting in a 76% DCR. The combination of exarafenib and binimetinib demonstrated significant pathway inhibition, as evidenced by reductions in phosphorylated extracellular signal-regulated kinase (pERK) and DUSP6 RNA expression in paired tissue biopsies. Additionally, substantial (>50%, up to 100%) reductions in circulating tumor DNA were observed in 70% of the combination-treated patients with NRAS mutant melanoma.As of September 18, 2023, exarafenib plus binimetinib was generally well-tolerated in two dose cohorts and cleared by a dose review committee. Exploration of the two final dose pairs for the combination regimen is underway. In the fourth quarter of 2023, the Company intends to select two doses for further development. Investigational KIN-8741: c-MET Inhibitor KIN-8741 is designed to be a highly selective c-MET inhibitor with broad mutational coverage, including acquired resistance mutations, in solid tumors driven by exon 14-altered and/or amplified c-MET. A primary focus for KIN-8741 is on non-small cell lung cancer, where the c-MET exon 14 alteration serves as the primary driver alteration. Kinnate expects to file an IND application for KIN-8741 with the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2023. Investigational Exarafenib Monotherapy: Pan-RAF Inhibitor Enrollment in the exarafenib monotherapy dose expansion phase of KN-8701 has been completed. As of September 11, 2023, the data cutoff, a total of 107 patients were enrolled in the monotherapy arm, with 71 patients receiving the expansion dose of 300 mg twice daily (bid). Among these patients, 3 achieved a PR and 26 demonstrated SD as their best response. As of the data cutoff, 26 patients with Class II-driven solid tumors were enrolled across both the dose escalation and dose expansion phases of KN-8701. Twenty-one of these patients received exarafenib as a monotherapy at 300 mg bid, with 7 patients continuing on therapy. Out of 8 patients with Class II fusion-driven solid tumors who received exarafenib at 300 mg bid, 3 showed radiographic tumor reductions, 2 of the 6 efficacy-evaluable patients achieved confirmed PRs, resulting in a 33% ORR, and the remaining 4 efficacy-evaluable patients achieved SD as their best response, yielding a 100% DCR. Among 13 patients with Class II non-fusion driven solid tumors treated with exarafenib at 300 mg bid, 7 patients experienced radiographic tumor reductions and 6 patients experienced SD as their best response, yielding a DCR of 60%. In addition, 1 patient treated at the 200 mg bid dose experienced a confirmed PR. Exarafenib, administered at a dose of 300 mg bid to a cohort of 71 patients, demonstrated a consistent safety profile in line with previous reporting. Treatment-related adverse events (TRAEs) were observed in 73% of patients, with 51% experiencing skin-related TRAEs, primarily comprising rash (28%), dermatitis acneiform (21%) and pruritis (11%). Reversible, asymptomatic liver enzyme elevations were observed, including Grade 3 elevations in alanine aminotransaminase (ALT; n=7 patients) and aspartate aminotransferase (n=6) and Grade 4 increased ALT (n=2). Other common TRAEs included Grade 1 and 2 asthenia and fatigue (13%), nausea (13% overall including 1 Grade 3 TRAE) and vomiting (8 overall including 1 Grade 3 TRAE). Overall, exarafenib was well-tolerated, with low rates of drug-related treatment interruption (27%), dose reductions (4%), and treatment discontinuations (9%). The mean dose intensity was 91%, with a median of 100%. These clinical data involving over 100 patients treated with exarafenib support its favorable safety and tolerability profile, which validates the successful execution of KN-8701. This profile is further supported by favorable pharmacokinetic/pharmacodynamic properties. Notably, the data showed higher response and disease control rates in patients with BRAF Class II fusion versus BRAF Class II non-fusion-driven cancers. However, limited anti-tumor activity was observed with exarafenib monotherapy across all patients with Class II alterations, which may be attributed to the significant heterogeneity of Class II alterations and the presence of other co-occurring mutations. Considering these results and the Company’s assessment of clinical development timelines for Class II fusion-driven solid tumors, Kinnate will not proceed with further clinical development of exarafenib as a monotherapy agent and will explore strategic alternatives. Investigational KIN-3248: FGFR Inhibitor As of September 11, 2023, the data cutoff, a total of 54 patients were enrolled in the ongoing dose escalation trial for KIN-3248, spanning 6 different dose levels: 5 mg once daily (QD) (dose level; DL 1), 10 mg QD (DL 2), 20 mg QD (DL 3), 30 mg QD (DL 4), 40 mg QD (DL 5) and 50 mg QD (DL 6). This includes 31 patients who have not been previously treated with an FGFR 2/3 inhibitor and 23 patients previously treated with an FGFR2/3 inhibitor. The predicted efficacious dose of 40 mg QD (DL 5) has been cleared, and further exploration is ongoing at the 50 mg QD dose (DL 6). Two PRs were observed, with 1 confirmed PR in a patient with pancreatic cancer who had not received prior treatment with an FGFR2 inhibitor; treatment began at 20 mg QD and was then increased to 30 mg QD. Seven patients are currently enrolled at doses of 40 mg QD or higher and have not yet reached their first scan.A dose-response relationship was observed in pharmacodynamic markers, including decreased pERK levels and increased serum phosphate levels.As of the data cut off, the maximum tolerated dose has not yet been determined. The safety and tolerability profile of KIN-3248 is consistent with other FGFR inhibitors in clinical development or currently approved. Kinnate will explore strategic alternatives for the KIN-3248 program. Investigational KIN-7136: MEK Inhibitor KIN-7136 is designed to be a brain-penetrant MEK inhibitor. Kinnate previously announced that the FDA cleared the IND application for KIN-7136. Based on the reprioritization plan, the Company will not initiate a clinical trial for KIN-7136 at this time. CDK4 Program Kinnate is exploring drug candidates (DC) for a potentially brain-penetrant, selective CDK4 inhibitor and expects to nominate a DC in the fourth quarter of 2023. Corporate Update Kinnate will implement a corporate restructuring by reducing the Company’s workforce by approximately 70%. The Company expects to have 28 remaining full-time employees. The Company is also taking related measures to reduce operating expenses. This includes separating from all employees of its wholly-owned subsidiary in China, Kinnjiu Biopharma. As of June 30, 2023, Kinnate had approximately $204.3 million in cash, cash equivalents and investments, which is anticipated to fund operations into at least the second quarter of 2026. About Kinnate Biopharma Inc. Kinnate Biopharma Inc. is a clinical-stage precision oncology company founded with a mission to inspire hope in those battling cancer by expanding on the promise of targeted therapies. The Company concentrates its efforts on addressing known oncogenic drivers for which there are currently no approved targeted drugs and to overcome the limitations associated with existing cancer therapies, such as non-responsiveness or the development of acquired and intrinsic resistance. The Company’s lead product candidates are investigational pan-RAF inhibitor, exarafenib, which targets cancers with BRAF and NRAS-driven alterations, and investigational FGFR inhibitor, KIN-3248, which is designed for cancers with FGFR2 and FGFR3 alterations. The Company also has early-stage programs, including a c-MET inhibitor that targets resistant variants. The Kinnate Discovery Engine drives the Company’s pipeline of small molecule candidates, prioritizing high selectivity, optimized pharmaceutical properties, broad genetic alteration coverage, overcoming resistance, and brain penetration. For more information, visit Kinnate.com and follow the Company on LinkedIn to learn about its most recent initiatives. Forward Looking Statements This press release contains forward-looking statements that involve substantial risks and uncertainties. These forward-looking statements include, without limitation, the Company’s intentions for exploring strategic alternatives; the plans for implementing a workforce restructuring and the anticipated effect of such action, including with respect to Kinnjiu Biopharma; the future plans for clinical development of exarafenib as a monotherapy; the timing and number of doses for further development for the exarafenib plus binimetinib combination; the clinical trial plans for KIN-7136; the timing for filing an IND for KIN-8741; the timing and plans for nominating a DC for the Company’s CDK4 program; the Company’s anticipated cash runway; and statements by our Chief Executive Officer. Words such as “believes,” “anticipates,” “intends”, “plans,” “expects,” “will,” “potential” and similar expressions are also intended to identify forward-looking statements. We have based these forward-looking statements largely on our current expectations and projections about future events and trends. Such expectations and projections may never materialize or may prove to be incorrect. These forward-looking statements are subject to a number of risks, uncertainties, assumptions and other factors, including, among other things: operating as a clinical-stage biopharmaceutical company with a limited operating history; the timing, progress and results of ongoing and planned preclinical studies and clinical trials for our current product candidates; that continued dose escalation in our clinical trials could increase the risk of the occurrence of adverse events; the potential for future clinical trial results to differ from initial results or from our preclinical studies; our ability to timely enroll a sufficient number of patients in our clinical trials; our ability to raise additional capital to finance our operations; our ability to discover, advance through the preclinical and clinical development of, obtain regulatory approval for and commercialize our product candidates; the novel approach we are taking to discover and develop drugs; our ability to timely file and obtain approval of IND applications for our planned clinical trials; negative impacts of the COVID-19 pandemic on our business, including ongoing and planned clinical trials and preclinical studies; competition in our industry; regulatory developments in the United States and other countries; our ability to attract, hire and retain highly skilled executive officers and employees; difficulties in managing our growth; our ability to protect our intellectual property; reliance on third parties to conduct our ongoing and planned preclinical studies and clinical trials, and to manufacture our product candidates; general economic and market conditions; and other risks. These and other risks, uncertainties, assumptions and other factors are further described under the heading “Risk Factors” in our Quarterly Report on Form 10-Q for the quarter ended June 30, 2023 that we filed with the Securities and Exchange Commission (SEC) on August 8, 2023, as well as in our subsequent filings we make with the SEC. New risk factors emerge from time to time and it is not possible for our management to predict all risk factors, nor can we assess the impact of all factors on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially from those contained in, or implied by, any forward-looking statements. Investors should not rely upon forward-looking statements as predictions of future events. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance or achievements. Our forward-looking statements speak only as of the date of this release, and except as required by law, we undertake no obligation to update publicly any forward-looking statements for any reason in the future. Company Contact:Investors@kinnate.com

近日，TOP期刊JMC更新了一篇AstraZeneca公司开发的透脑KRAS G12C抑制剂AZD4747的发现过程。如图1，根据AZ自研的G12C抑制剂AZD4625，去除嘧啶并环降低了分子的平面性，并引入炔甲基得到高CNS暴露的AZD4747（临床前阶段）。图1  从AZD4625到AZD4747KRAS G12C抑制剂的赛道非常拥挤，目前正在评估多种药物。已经上市的有AMG510和MRTX849，国内外还有多款抑制剂处于临床阶段。除了下图2公开结构的基因泰克的GDC-6036、诺华的JDQ443、以及AZD4625，还有临床试验中尚未披露结构的包括LY3537982(礼来公司)、BI 1823911(勃林格殷格翰公司)和D-1553 (InventisBio公司)。礼来早期分子LY3499446和强生的JNJ-74699157均因毒性而终止临床试验。KRAS的其他亚型如G12D、G12V、G13D等也都在火热开发中，panKRAS和RAS on抑制剂也是热点。2023年7月4日，加科思发布公告，艾伯维基于资产组合与战略决策原因，就双方合作协议发出终止通知，退回SHP2抑制剂的全球权益。诺华SHP2抑制剂单药临床失败已久，加科思权益被退也是迟早的事。KRAS抑制剂与SHP2抑制剂的联用似乎已经成为SHP2的救命稻草。图2  代表性的KRASG12C抑制剂据安进财报，sotorasib 2021年、2022年销售额分别为0.9亿美元和2.85亿美元。已低于华尔街分析师早前的预测。在临床中，Sotorasib和Adagasib的缓解率均在40%左右，无进展生存期（PFS）中位数改善约6个月。对于靶向突变的特异性治疗来说，这不是一个理想的数据，也不如其他靶向药物（如EGFR和ALK抑制剂）观察到的结果。并且已经出现了对治疗的耐药，耐药机制是多种多样的，包括KRAS、NRAS、BRAF、EGFR、FGFR2、MYC等基因突变。在KRAS和NRAS以及MEK等下游效应物中都观察到基因扩增和点突变，导致直接抵抗抑制或通过旁路信号通路重新激活。先天和潜在获得性耐药的另一个关键机制是中枢神经系统(CNS)转移性疾病的存在，特别是对于不能透脑的药物。例如，转移性脑疾病是NSCLC的一个普遍特征，发生在高达20%的患者中。颅内疾病的控制可以通过放疗来实现，但毒性很大。CNS转移在KRASG12C阳性NSCLC中也很常见，高达28%的患者在诊断时可检测到中枢疾病，随访时发生率上升至40%。因此，能入脑的KRAS G12C抑制剂具有差异化的临床优势。在中枢神经系统中实现药物暴露是一个长达数十年的挑战，比简单地实现口服暴露要困难得多。这是因为血脑屏障是对外源药物的强大屏障，它表达高水平的外排转运蛋白和紧密的细胞内连接，阻止大多数药物被动渗透。AZ总结出早期筛选入脑药物一般需要保持分子量(MW) < 450，极性表面积(PSA) < 90 Å2、LogD在1-4之间，也有总结需要更严格的PSA < 70 Å2。进一步提升入脑则需要PSA < 90 Å2，氢键供体(HBD) < 3, LogD在2 ~ 5范围内，MW <500。目前提出的CNS药物设计指南包括PSA < 76 Å2(但优选在25 - 60 Å2范围内)和HBD < 3(理想情况下为0或1)。Sotorasib (MW = 561, PSA = 92 Å2)，HBD = 1, Log D = 2.3)和Adagasib (MW = 604, PSA = 71 Å2，HBD = 0, Log D =3.6)距离这些理想的特性还很远。AZ开发针对脑转移癌症的成功上市和进入临床的案例也有许多，包括突变型EGFR激酶抑制剂osimertinib（上市）、EGFR激酶抑制剂AZD3759（申请上市）、ATM激酶抑制剂AZD1390（临床I期）、PARP1选择性抑制剂AZD9574（临床I/II期）。此外，还有迪哲的HER2小分子抑制剂DZD1516（临床I期），迪哲为阿斯利康的合资企业。图3  化合物14（AZD4747）的PK数据经过多轮优化，AZ最终确定了候选分子AZD4747，其KRAS G12C IC50=15 nM，Log D7.4= 2.9，PSA = 53 Å2，HBD = 1，因减掉一个嘧啶环，分子量也减少为441。AZD4747具有药物进入CNS系统的分子特性，对人P-gp和BCRP的体外外排较低。如图3，在啮齿类动物中，观察到的清除率从中等到高，小鼠和大鼠的肝血流量分别为52%和75%。小鼠的口服生物利用度(58%)高于大鼠(18%)。在犬中，观察到的清除率低至肝脏血流量的18%，口服生物利用度为63%。种群间稳态分布体积适中，为1.7 ~ 2.9 L/kg。虽然在大鼠体内得到的脑内Kpu,u为0.1低于预期，犬的Kpu,u为0.7和猴子的Kpu,u为1.6，达到了筛选标准。图4  AZD4747在KRASG12C NCI−H358异种移植模型中的疗效和PD如图4，在动物模型中验证了AZD4747的药效，小鼠每天口服AZD4747，剂量为100mg /kg、30mg /kg和10mg /kg对KRAS G12C突变体H358异种移植瘤的生长有良好的耐受性，并且在较高剂量下具有显著的消退作用，游离血浆中AZD4747的浓度随剂量呈线性关系。用AZD4747处理的小鼠肿瘤显示出DUSP6（受RAS/MAPK通路活性调控）表达的强烈、剂量和暴露依赖性下降。以KRAS、AstraZeneca为关键词在智慧芽专利数据库中搜索，主要查询到4篇WO专利：WO2020178282、WO2019215203、WO2019110751、WO2018206539。后三篇专利与KRAS的入脑抑制剂关系不大，其中专利WO2020178282实施例85和86之一即为AZD4747，化合物85和86为两个轴手性异构体。只测了86的活性和外排数据，86应该为AZD4747。转染的细胞系MDCK_MDR1_BCRP表达了两种主要的外排泵，这两种泵积极地排除化合物穿过血脑屏障的转运，通过该方法测量的具有2或更小的外排比的化合物被确定为具有良好血脑屏障渗透特性的潜力。图5所示的化合物都有潜力，后续根据其他评价数据确定了化合物86具有均衡的成药潜力。专利WO2020178282的最早优先权日为2019年3月5日，国际申请时间为2020年3月3日，国际公布日为2020年9月10日，国内公开文本CN113508118A预期到期时间为2040年3月3日。图5  WO2020178282中公开的外排数据在目前两个KRAS G12C上市药物中，在已发表的sotorasib研究中，临床试验排除了CNS转移活跃的患者，因此关于sotorasib中枢神经系统渗透的数据有限。Sabari及其同事首先对KRAS突变NSCLC患者的脑转移进行了回顾性分析，然后对adagrasib的药理学和临床前数据进行了全面回顾，在多个临床前脑脊髓炎模型中，adagrasib渗透到脑脊液中，显示出肿瘤消退和延长生存期。在2例非小细胞肺癌和未经治疗的脑脊髓炎患者中，adagrasib脑脊液浓度高于靶细胞IC50。这两名患者均表现出相应的脑转移，支持adagrasib在脑中的潜在临床活性。只有2名脑转移患者的数据，也遭到外界批评。主要是因为脑转移的治疗和预防对患者预后至关重要。这些数据支持adagrasib在KRAS G12C突变的非小细胞肺癌合并未经治疗的脑转移患者中的进一步发展（NCT03785249）。该项I/II期临床试验招募了822名患者，评估MRTX849 (adagasib)在KRAS G12C突变的晚期实体肿瘤患者中的安全性、耐受性、药物水平、分子效应和临床活性，预计完成时间为2024年9月。此外，益方生物开发的D-1553在临床试验也发现，在3名存在基线脑转移的患者中，1名幸运的患者达到部分缓解，客观缓解率17%，接受治疗前脑部的转移灶已经超过了20mm，接受治疗后肿瘤病灶缩小了近一半，另外2名病情稳定，疾病控制率高达100%。当然，发生癌症脑转移的患者也有可能因为CNS系统遭到破坏，血脑屏障功能受损，使得临床前动物模型评估中不能入脑的化合物，在临床试验中具有透脑的功效。AZ有着多款入脑药物成功开发的经验，期待AZ的研究能够进一步给临床患者带来获益。参考资料：1.Oliver Steward et.al; Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration.doi.org/10.1021/acs.jmedchem.3c00746.2.Nagasaka et al;Penetrating the central nervous system sanctuary of KRAS, a target once thought “undruggable”.Transl Lung Cancer Res 2023;12(4):665-668.3.专利 WO2020178282、CN113508118A公开文本.4.https://clinicaltrials.gov/study/NCT03785249?term=NCT03785249&rank=1.5.智慧芽新药情报数据库.

▎药明康德内容团队编辑KRAS是最早发现的癌症基因之一，其突变在癌症患者中很常见。但在很长一段时间里，致癌性的KRAS蛋白被认为是靶向治疗的“不可成药”靶点。这种情况随着KRAS G12C抑制剂Lumakras（sotorasib）与Krazati（adagrasib）的获批开始发生改变。但G12C只是KRAS的众多突变形式之一，而sotorasib与adagrasib的适应症肺癌也不过是与这些致癌突变相关的众多癌症之一。在发现KRAS G12C抑制剂之后，科学家们已经将目标转向其它KRAS突变体，旨在开发出能够靶向多种、甚至全部KRAS突变体的泛KRAS（pan-KRAS）靶向疗法，为携带KRAS突变的诸多癌症类型提供治疗选择。近日发表在《自然》杂志上的一篇论文中，美国纪念斯隆-凯特琳癌症中心（Memorial Sloan Kettering Cancer Center）的研究人员发布了一种新抑制剂分子的积极结果，可以有效阻断更多突变形式的KRAS蛋白。克服“不可成药”挑战，找到全能型抑制剂由KRAS突变驱动的癌症长期以来一直被认为是不可成药的，因为KRAS蛋白的表面光滑，缺乏适合小分子抑制剂结合的“口袋”结构，因此很难找到一种靶向药物分子来插入KRAS蛋白结构并抑制其活性。直到十年前，研究人员发现G12C突变的KRAS蛋白有一个小口袋结构，该结构通过与GTP发生可逆性结合来调节KRAS蛋白的活性（与GTP结合）/非活性（与GDP结合）状态。基于这一发现，研究人员开发出了可以进入“口袋”、并将KRAS G12C蛋白“锁定”在非活性状态的药物。但是这些药物对其他没有口袋结构的KRAS突变形式无效。为了解决这一问题，研究人员开始着手研发不限KRAS蛋白突变形式的小分子泛KRAS抑制剂。他们通过对一种已知的KRAS G12C共价强效抑制剂BI-0474进行结构修饰改造，并最终筛选优化得到了本研究的目的分子——BI-2865。BI-2865分子比前体分子更强效地抑制了携带KRAS G12C/G12D/G12V突变的BaF3细胞的增殖。在表达KRAS G12C的BaF3细胞中，BI-2865的效果与BI-0474和sotorasib相当。不过，当BaF3细胞在IL3存在的条件下接受BI-2865处理时，研究者们观察到的抗增殖效应很小。▲本研究中候选分子的化学结构式（图片来源：参考资料[1]）受到这些观察结果的鼓舞，研究人员进一步研究了BI-2865及其相关化合物在多种肿瘤类型中的抗癌效果。在体外细胞实验中，该化合物有效抑制了多种野生型和KRAS突变肿瘤细胞系中KRAS蛋白激活以及其下游信号传导的能力，这些细胞系源自肺癌、结肠癌或胰腺癌。当在人类胚肾293（HEK293）细胞中单独表达时，该抑制剂分子也能够使癌症中发现的24种最常见的KRAS突变蛋白中的18种失活。不仅如此，研究人员还发现，常见的KRAS突变蛋白在癌细胞中进行核苷酸循环——这是药物进入GDP结合型KRAS蛋白结构的必要条件，而不是固定在活跃状态，而且KRAS突变蛋白的循环动力学比野生型KRAS慢。这一发现更新了以往人们对KRAS突变蛋白的认知。“我们对BI-2865能够灭活最常见的致癌KRAS突变蛋白感到惊讶，”该研究的第一作者Dongsung Kim博士在谈及这些发现时说道，“这些突变蛋白被认为在癌症中处于活跃状态，但如果这是真的，那么这种药物将完全不起作用。这项研究为我们理解KRAS突变如何引起癌症开辟了一个新的方向。”事实上，研究结果表明，除了G12C突变之外，新的抑制剂还能够阻断其他类型KRAS突变蛋白的活性。创新作用机制，不针对特定突变的“泛KRAS”抑制剂进一步的研究发现，BI-2865通过选择性地与仅在非活性状态下存在的KRAS蛋白表面上的口袋结构来靶向KRAS发挥作用，同时保留NRAS和HRAS的活性。这是基于RAS亚型的GTPase结构域的进化差异，虽然KRAS、NRAS和HRAS的GTPase结构域高度同源，但这些蛋白之间也有少数非同源氨基酸的存在，这些非同源氨基酸赋予了KRAS正构/变构区域的特殊性。在实验中，BI-2865以高亲和性优先与KRAS的非活性状态结合，但不与NRAS或HRAS结合。由于HRAS、NRAS可有效被激活和代偿KRAS的功能，该抑制剂分子对野生型细胞增殖能力的影响也很小，有助于减少潜在的治疗副作用。这种结合也能够稳定KRAS的非活性构象，防止它与下游效应物相互作用，从而阻断致癌信号。此外，BI-2865不与KRAS形成共价键，这与以前通过抑制KRAS功能来发挥疗效的KRAS抑制剂有着明显区别。这种作用机制的好处在于它不需要与特定的突变氨基酸共价结合，有望同时对多种KRAS突变蛋白发生作用。图片来源：123RF将“泛KRAS”抑制剂分子推向临床，还有多远的路要走？在本研究中，BI-2865有效阻断了多种癌细胞系（包括肺癌、结肠癌和胰腺癌）的生长，它在KRAS基因突变引起的肺癌和结直肠癌小鼠模型中也有效。BI-2865的结构类似物（结构经优化后适用于体内给药）在携带KRAS G12C、G12D、G12V和A146V突变的小鼠中显著减弱了肿瘤生长，并且没有对小鼠造成明显的毒性。BI-2865的抗肿瘤作用与其良好的药代动力学特性相关，血浆和肿瘤中的药物暴露量、肿瘤模型中ERK磷酸化和DUSP6 mRNA表达的一致抑制证明了这一点。鉴于BI-2865在临床前研究中的良好表现，研究人员正在筹划将其推进至临床研究阶段。BI-2865是由勃林格殷格翰（Boehringer Ingelheim）的研究人员开发的，但该分子只是一种原型药分子（prototype），在患者身上进行临床试验之前需要对其加以改进，勃林格殷格翰目前正在针对BI-2865的临床开发进行优化。纪念斯隆-凯特琳癌症中心的研究人员表示，他们也将与勃林格殷格翰的研究团队保持密切合作，以期在未来一年内制造出可以用于临床试验的药物。KRAS是癌症中最常见的突变蛋白之一，其成药性难题一直以来是生物医药行业的一大“圣杯”。本研究无疑是KRAS癌症疗法开发的又一突破，其所发现的泛KRAS抑制剂更是值得在KRAS基因突变驱动的癌症患者中进行深入的临床开发。倘若成功，它将为广大癌症患者带来福音。同时，该研究所揭示的创新药理机制为开发针对KRAS以及其他致癌蛋白的新癌症疗法奠定了坚实的基础。参考资料：[1] Kim, D., Herdeis, L., Rudolph, D. et al. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth. Nature (2023). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-023-06123-3[2] Potential Drug Shows Promise Targeting a Range of KRAS-Driven Cancers in the Lab，Retrieved June 13, 2023, from https://www.mskcc.org/news/potential-drug-shows-promise-targeting-range-of-kras-driven-cancers-in-lab本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。