Structure-based discovery of SIAIS001 as an oral bioavailability ALK degrader constructed from Alectinib

Fusion proteins of the anaplastic lymphoma kinase (ALK) are promising therapeutic targets for cancer and other human diseases, especially for non-small cell lung cancer (NSCLC) and anaplastic large-cell lymphomas (ALCLs). We described herein a structure-based design, synthesis, and evaluation of ALK PROTACs (proteolysis-targeting chimeras) based on Alectinib as the warhead. We firstly screened CRBN ligands as the E3 ligase moiety, then obtained a series of potent ALK degraders based on different CRBN ligands, exemplified by SIAIS091 and SIAIS001 with lenalidomide/thalidomide-based linkers. Both of them induced effective ALK degradation at low nanomolar concentrations in cells, and showed much better growth inhibition effects than Alectinib. SIAIS091 or SIAIS001 also promoted cell cycle arrest in G1/S phase. Finally, SIAIS001 exhibited good oral bioavailability in Pharmacokinetics study. READ ARTICLE

European Journal of Medicinal Chemistry DOI:10.1016/j.ejmech.2021.113335

Authors: Chaowei Ren, Ning Sun, Ying Kong, Xiaojuan Qu, Haixia Liu, Hui Zhong, Xiaoling Song, Xiaobao Yang, Biao Jiang

Pre-ClinicalKirk SmithMay 5, 2021Anaplastic lymphoma kinase (ALK), Proteolysis targeting chimeras, Alectinib, CRBN, Anaplastic large-cell lymphomas (ALCL), Oral bioavailability

Oral coadministration of elacridar and ritonavir enhances brain accumulation and oral availability of the novel ALK/ROS1 inhibitor lorlatinib

Lorlatinib, a novel generation oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor with high membrane and blood-brain barrier permeability, recently received accelerated approval for treatment of ALK-rearranged non-small-cell lung cancer (NSCLC), and its further clinical development is ongoing. We previously found that the efflux transporter P-glycoprotein (MDR1/ABCB1) restricts lorlatinib brain accumulation and that the drug-metabolizing enzyme cytochrome P450-3A (CYP3A) limits its oral availability. Using genetically modified mouse models, we investigated the impact of targeted pharmacological inhibitors on lorlatinib pharmacokinetics and bioavailability. Upon oral administration of lorlatinib, the plasma AUC0-8h in CYP3A4-humanized mice was ∼1.8-fold lower than in wild-type and Cyp3a–/– mice. Oral coadministration of the CYP3A inhibitor ritonavir caused reversion to the AUC0-8h levels seen in wild-type and Cyp3a–/– mice, without altering the relative tissue distribution of lorl..... READ ARTICLE

European Journal of Pharmaceutics and Biopharmaceutics
DOI:10.1016/j.ejpb.2019.01.016

Authors: Wenlong Li, Rolf W. Sparidans, Yaogeng Wang, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel

Pre-ClinicalKirk SmithMarch 1, 2019Lorlatinib, Cytochrome P450-3A, Oral bioavailability, Ritonavir, P-glycoprotein, Oatp1a/1b