Merck对Wee1抑制剂缺乏信心？
9月11日，Merck宣布将MK-1775转让给AstraZeneca，协议如下：AstraZeneca will pay Merck a $50 million upfront fee. In addition Merck will be eligible to receive future payments tied to development and regulatory milestones, plus sales-related payments and tiered royalties. AstraZeneca will be responsible for all future clinical development, manufacturing and marketing.
MK-1775是一种WEE1激酶抑制剂，联合其他化疗药物治疗卵巢癌，目前处于IIa期临床。虽然有里程金、销售分成，但在5000万美元这个价位转让MK-1775实在有点偏低，要知道买方是饥不择食的AstraZeneca。MK-1775是作用机制全新的药物，属于first-in-class不说，这个靶点的竞争程度很低（还有一个是Pfizer的PD0166285），如果成功应该有不错的市场前景。Merck不再参与MK-1775的后续研究，等于完全放弃在这个靶点上取得的领先地位。虽然Merck声称要将精力集中到anti-PD1单抗lambrolizumab和长春新碱衍生物vintafolide，但我不相信它会舍得把好的项目卖出去，更大的原因可能是对Wee1抑制剂缺乏信心。
MK-1775通过与Wee1结合而阻碍CDK1的磷酸化，进而抑制癌细胞DNA修复，与诱导DNA损伤的化疗药物如吉西他滨、铂类产生协同作用。从这个层面上来说，MK-1775的治疗潜力是非常巨大的，不仅能增强许多化疗药物的疗效，还能作为放疗的辅助药物。
DNA损伤修复是广泛存在的，Wee1抑制剂区分癌细胞、正常细胞的关键是p53，文献（Mol Cancer Ther. 2009, 8, 2992-3000.）中有经典论述：
p53 is a key regulator of the G1 checkpoint and is one of the most frequently mutated genes in cancer. Therefore, a majority of human cancers lack G1 checkpoint but retain the S- and G2-phase checkpoints. As a result, p53-deficient cells are predicted to be more dependent on S or G2 checkpoint. Hence, p53-deficient tumors treated with G2 checkpoint abrogator may be particularly susceptible to DNA damage. Nontumor tissue will retain G1 checkpoint activity due to its normal p53 pathway function. Thus, checkpoint escape induced by G2-checkpoint abrogator may selectively sensitize p53-deficient cells to DNA-damaging anticancer agents while sparing normal tissues from toxicity.
ASCO2009公布了MK-1775的I期临床结果（J Clin Oncol. 2009, 27 (15S), 3510.），采用100、200、325、650、1300 mg剂量递增方案，单用或联合吉西他滨、顺铂、卡铂，37例患者中4例出现剂量限制性毒性，最大耐受剂量在200-325 mg，半衰期为7.6-12.2 h。
在联合卡铂治疗卵巢癌的II期临床试验中，MK-1775的口服剂量是225 mg，这已经超过I期临床报道的最大耐受剂量。因此，个人觉得Merck放弃该药的主要原因是安全性问题，后期研发风险太大。另一方面，MK-1775过分依赖p53，大大限制了它的临床应用。
转载 疑夕新浪博客
阿斯利康购买默克肿瘤药物MK-1775的授权
AstraZeneca pays $50 million for rights to Merck cancer drug
Merck & Co Inc has licensed its experimental cancer drug to AstraZeneca Plc for a $50 million upfront fee in a deal that shows Britain's second-biggest drugmaker continuing to rebuild its pipeline. Under the terms of the agreement, Merck, the No. 2 U.S. drugmaker, will also be eligible to receive future payments related to development and regulatory milestones, as well as tiered royalties. The drug, MK-1775, is currently in mid-stage trials in combination with standard-of-care therapies for the treatment of patients with certain types of ovarian cancer.
每天都能看到新消息，真是感谢楼主 都是巨头，相关信息肯定都知根知底，阿斯利康也不傻 呵呵，不是傻不傻的问题，只是说没信心，不太愿意冒这个风险。阿斯利康和默克估计都有自己的考虑。 dejunchem 发表于 2013-9-12 20:44 static/image/common/back.gif
呵呵，不是傻不傻的问题，只是说没信心，不太愿意冒这个风险。阿斯利康和默克估计都有自己的考虑。 ...
呵呵，商业公司考虑是利润最大化，也不是什么信心不信心的问题
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