Development of covalent PIP4K2 inhibitors for the treatment of p53 deficient lung tumors

 描述（由申请人提供）：肿瘤抑制基因TP 53（编码p53）的缺失或突变是癌症中最常见的事件之一。临床和功能研究已经明确证实了癌症中p53缺失的功能重要性，但不幸的是，没有小分子方法来解决这一挑战。我们的实验室最近已经证明，由PIP 4 K2 A和PIP 4 K2 B基因编码的2型磷脂酰肌醇-5-磷酸4-激酶A和B（PIP 4 K2 A和B）的激酶活性对于具有TP 53缺失的癌症的生长至关重要。具体地，我们已经证明，小鼠中PIP 4K 2A和PIP 4K 2B的生殖系缺失在TP 53缺失的情况下抑制肿瘤形成，并且原型抑制剂选择性地杀死携带TP 53缺失的细胞。的目标 该建议是开发第一种具有必需的效力、选择性和药理学性质的共价PIP 4K 2抑制剂，以研究PIP 4K 2作为肺癌和其它以p53功能丧失和高水平PIP 4K 2为特征的疾病的治疗靶点的潜力。我们已经开发了一种原型共价PIP 4K 2抑制剂THZ-2-72-1，其不可逆地靶向PIP 4K 2并选择性地抑制p53缺陷型肺癌细胞系的增殖。 我们将使用一种集中的药物化学方法，通过建模和共晶体结构来开发优化的抑制剂，这些抑制剂可以使用异种移植，基因工程和primagraft模型来测试其抑制TP 53缺陷肿瘤生长的能力。这些研究将有助于验证PIP 4K 2作为新靶点的可行性，并将提供原型药物，这些药物可以进一步优化以用于最终的临床测试。

 DESCRIPTION (provided by applicant): Loss or mutations in the tumor suppressor gene TP53 (encoding p53) is one of the most frequent events in cancer. Clinical and functional studies have unequivocally validated the functional importance of the loss of p53 in cancer but unfortunately there are no small molecule approaches to address this challenge. Our labs have recently demonstrated that the kinase activity of type 2 phosphatidylinositol-5-phosphate 4-kinase A and B (PIP4K2A and B) encoded by PIP4K2A and PIP4K2B genes are crucial for the growth of cancers that harbor TP53 deletions. Specifically we have demonstrated that germ line deletion of PIP4K2A and PIP4K2B in mice suppresses tumor formation in the context of TP53 deletion and that prototype inhibitors selectively kill cells harboring TP53 deletions. The goal of this proposal is to develop the first covalent PIP4K2 inhibitors with the requisite potency, selectivity and pharmacological properties to interrogate the potential of PIP4K2 as a therapeutic target in lung cancer and other diseases characterized by loss of p53 function and high level of PIP4K2s. We have developed a prototype covalent PIP4K2 inhibitor, THZ-2-72-1, which irreversibly targets PIP4K2 and selectively inhibits the proliferation of p53 deficient lung cancer cell lines. We will use a focused medicinal chemistry approach informed by modeling and co-crystal structures to develop optimized inhibitors that can be tested using xenograft, genetically engineered and primagraft models for their ability to inhibit TP53-deficient tumor growth. These studies will serve to pharmacologically validate PIP4K2 as a new target and will provide prototype drugs that can be further optimized for eventual clinical testing.