Design, synthesis and biological evaluation of novel quinazolinone derivatives as CRBN E3 ligase modulators.

CRBN E3 ligase modulators, also anteriorly called immunomodulatory drugs (IMiDs), exhibit excellent pharmacological activity by degrading cereblon (CRBN) associated multiple substrates and have become an important field for drug development. These modulators such as Thalidomide, Lenalidomide and CC-122 abduct CRBN to adhere to IKZF1/3 and other neosubstrates, and then induce the degradation of these substrates, thus retarding the further development of related diseases. Herein, we reported a series of CC-122 derivatives that inhibit the proliferation of hematological malignant tumor cell lines. Studies further confirmed that several derivatives which exhibit strong anti-proliferation effect induce the significant degradation of IKZF1/3. In addition, we found that the best compound 14 (SIAIS355035) exhibits better degradation activity and better anti-proliferation activities than CC-122, especially in diffuse large B lymphoma cell lines. Moreover, the PK properties of compound 14 are pretty promising with excellent oral bioavailability. These results clarified the SAR of CC-122 derivatives preliminarily and suggested that compound 14 has great value for further studies as an ideal novel CRBN E3 ligase modulation drug.

Treatment of hospital wastewater by electron beam technology: Removal of COD, pathogenic bacteria and viruses.

The effective treatment of hospital sewage is crucial to human health and eco-environment, especially during the pandemic of COVID-19. In this study, a demonstration project of actual hospital sewage using electron beam technology was established as advanced treatment process during the outbreak of COVID-19 pandemic in Hubei, China in July 2020. The results indicated that electron beam radiation could effectively remove COD, pathogenic bacteria and viruses in hospital sewage. The continuous monitoring date showed that the effluent COD concentration after electron beam treatment was stably below 30 mg/L, and the concentration of fecal Escherichia coli was below 50 MPN/L, when the absorbed dose was 4 kGy. Electron beam radiation was also an effective method for inactivating viruses. Compared to the inactivation of fecal Escherichia coli, higher absorbed dose was required for the inactivation of virus. Absorbed dose had different effect on the removal of virus. When the absorbed dose ranged from 30 to 50 kGy, Hepatitis A virus (HAV) and Astrovirus (ASV) could be completely removed by electron beam treatment. For Rotavirus (RV) and Enterovirus (EV) virus, the removal efficiency firstly increased and then decreased. The maximum removal efficiency of RV and EV was 98.90% and 88.49%, respectively. For the Norovirus (NVLII) virus, the maximum removal efficiency was 81.58%. This study firstly reported the performance of electron beam in the removal of COD, fecal Escherichia coli and virus in the actual hospital sewage, which would provide useful information for the application of electron beam technology in the treatment of hospital sewage.

Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile.

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation.

Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance.

EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.

Design, Synthesis, and Evaluation of Tetrahydropyrrolo[1,2-c]pyrimidines as Capsid Assembly Inhibitors for HBV Treatment.

The discovery of novel tetrahydropyrrolo[1,2-c]pyrimidines derivatives from Bay41_4109 as hepatitis B virus (HBV) inhibitors is herein reported. The structure-activity relationship optimization led to one highly efficacious compound 28a (IC50 = 10 nM) with good PK profiles and the favorite L/P ratio. The hydrodynamic injection model in mice clearly demonstrated the efficacy of 28a against HBV replication.