From Pyrazolones to Azaindoles: Evolution of Active-Site SHP2 Inhibitors Based on Scaffold Hopping and Bioisosteric Replacement

The tyrosine phosphatase SHP2 controls the activity of pivotal signaling pathways, including MAPK, JAK-STAT, and PI3K-Akt. Aberrant SHP2 activity leads to uncontrolled cell proliferation, tumorigenesis, and metastasis. SHP2 signaling was recently linked to drug resistance against cancer medications such as MEK and BRAF inhibitors. In this work, we present the development of a novel class of azaindole SHP2 inhibitors. We applied scaffold hopping and bioisosteric replacement concepts to eliminate unwanted structural motifs and to improve the inhibitor characteristics of the previously reported pyrazolone SHP2 inhibitors. The most potent azaindole 45 inhibits SHP2 with an IC50 = 0.031 μM in an enzymatic assay and with an IC50 = 2.6 μM in human pancreas cells (HPAF-II). Evaluation in a series of cellular assays for metastasis and drug resistance demonstrated efficient SHP2 blockade. Finally, 45 inhibited proliferation of two cancer cell lines that are resistant to cancer drugs and diminished ERK signaling.酪氨酸磷酸酶SHP2（tyrosine phosphatase SHP2）可调控包括丝裂原活化蛋白激酶（MAPK）、JAK-STAT以及磷脂酰肌醇3-激酶-蛋白激酶B（PI3K-Akt）在内的关键信号通路活性。异常的SHP2活性会导致细胞增殖失控、肿瘤发生及转移。近期研究表明，SHP2信号通路与MEK、BRAF抑制剂等抗癌药物的耐药性密切相关。本研究中，我们开发了一类新型氮吲哚（azaindole）类SHP2抑制剂。我们采用骨架跃迁（scaffold hopping）与生物电子等排替换（bioisosteric replacement）策略，以剔除冗余的结构基序，并优化此前报道的吡唑酮（pyrazolone）类SHP2抑制剂的性能。活性最优的氮吲哚类化合物45在酶学实验中对SHP2的半数抑制浓度（IC50）为0.031 μM，在人胰腺癌细胞（HPAF-II）中的半数抑制浓度为2.6 μM。通过一系列针对转移与耐药性的细胞实验评估，该化合物可实现高效的SHP2信号阻断。最终，化合物45能够抑制两类对抗癌药物耐药的癌细胞系的增殖，并减弱细胞外调节蛋白激酶（ERK）信号通路的活性。