Advances in targeting EGFR allosteric site as anti-NSCLC therapy to overcome the drug resistance

Lung and bladder cancers are mostly incurable because of the early development of drug resistance and metastatic dissemination. Hence, improved therapies that tackle these two processes are urgently needed to improve clinical outcome. We have identified RSK4 as a promoter of drug resistance and metastasis in lung and bladder cancer cells. Silencing this kinase, through either RNA interference or CRISPR, sensitized tumor cells to chemotherapy and hindered metastasis in vitro and in vivo in a tail vein injection model. Drug screening revealed several floxacin antibiotics as potent RSK4 activation inhibitors, and trovafloxacin reproduced all effects of RSK4 silencing in vitro and in/ex vivo using lung cancer xenograft and genetically engineered mouse models and bladder tumor explants. Through x-ray structure determination and Markov transient and Deuterium exchange analyses, we identified the allosteric binding site and revealed how this compound blocks RSK4 kinase activation through binding to an allosteric site and mimicking a kinase autoinhibitory mechanism involving the RSK4’s hydrophobic motif. Last, we show that patients undergoing chemotherapy and adhering to prophylactic levofloxacin in the large placebo-controlled randomized phase 3 SIGNIFICANT trial had significantly increased (P = 0.048) long-term overall survival times. Hence, we suggest that RSK4 inhibition may represent an effective therapeutic strategy for treating lung and bladder cancer.

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Allosteric inhibitors of SHP2: an updated patent review (2015-2020)

Current Medicinal Chemistry ◽

10.2174/1568011817666200928114851 ◽

2020 ◽

Vol 27 ◽

Author(s):

Jingwei Wu ◽

Huan Zhang ◽

Guilong Zhao ◽

Runling Wang

Keyword(s):

Drug Resistance ◽

Chemical Structure ◽

Therapeutic Strategy ◽

Allosteric Site ◽

Allosteric Inhibitors ◽

Ptpn11 Gene ◽

Over Expression ◽

Patent Review ◽

Low Toxicity ◽

Orally Bioavailable

: Srchomology-2-domain-containing PTP 2 (SHP2) is a nonreceptor phosphatase encoded by the PTPN11 gene. Over expression of SHP2 is associated with various human diseases, such as Noonan syndrome, LEOPARD syndrome, and cancers. To overcome the shortcomings of existing orthosteric inhibitors, novel inhibitors targeting the allosteric site of SHP2 with high selectivity and low toxicity are under development. This paper reviews allosteric inhibitors of SHP2 published in patents from 2015 to 2020. The molecules are classified according to the chemical structure of the central core. SHP2 has long been considered as an ‘undruggable’ protein. Fortunately, a critical breakthrough was made by researchers from Novartis AG Ltd., who identified SHP099 as a highly potent, selective, soluble, and orally bioavailable SHP2 allosteric inhibitor. Currently, there are several allosteric inhibitors of SHP2 in clinical development. However, drug resistance is still a major challenge. The combination of SHP2 allosteric inhibitors and immunotherapy drugs or molecular targeted drugs is emerging as a promising therapeutic strategy against drug resistance.

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