Metabolism-based structure optimization: Discovery of a potent and orally available tyrosine kinase ALK inhibitor bearing the tetracyclic benzo[b]carbazolone core

Abstract

A metabolism-based fine-tuning structure-optimization was conducted to address the oxidative metabolism and hERG blockade of our early ALK inhibitor. Compound 8 was identified showing high potency against both ALK wild type and gatekeeper mutant. In addition to the optimal PK properties and significant cell antiproliferative effects, 8 showed complete tumor growth inhibition at doses of 50 or 10mg/kg once daily in the Karpas299 xenograft model. All these results encouraged the further development of 8 as a potent and orally bioavailable ALK inhibitor.

LNL-Carbazole Pincer Ligand: More than the Sum of Its Parts

“…The rigid and stable planar heterocycle boasts with proficient electron donating ability, charge transfer functionality, and excellent biocompatibility. ,,, Its efficient hole transporting capability ,, has equated to carbazoles’ success in the fields of photo- − ,,, and electrochemistry, ,,− also in donor–acceptor systems crucial toward preparation of organic light emitting diodes (OLEDs) ,− with photoswitching ability . The smart electro- and photoactive application of carbazole extends further, with successful utilization in polymers and semiconducting polymers, ,,,− electrochemiluminescence, and tailor-made photo­(redox) catalysis. − Carbazole-based organic compounds have also featured prominently in the field of medicinal chemistry spanning application as anticancer, ,− antifungal, ,, antioxidant, , antiviral, anti-inflammatory, , and antibacterial agents. ,,, …”

Identification of 1H-pyrazolo[3,4-b]pyridine derivatives as potent ALK-L1196M inhibitors

“…The ALK gatekeeper mutation L1196M is the most frequent secondary mutation taking place in NSCLC patients and, consequently, a significant effort has been made to identify novel and potent L1196M inhibitors 31 . These efforts have led to the development of second-generation ALK inhibitors including ceritinib 32,33 , alectinib 10 , lorlatinib [8][9] , brigatinib 34,35 , ensartinib 36 and entrectinib 11 that circumvent the acquired secondary mutations 21,37 (Figure 1).…”