As of the end of 2023, of the 102 approved drugs and reported clinical candidates that are MCs, ten are kinase modulators (Table ), of which eight are orally bioavailable and two are administered parenterally (Figure ). Of the eight oral compounds, five are nucleotide site binders that are Rule-of-5 9 compliant and that seemingly were developed from non-macrocyclic precursors; these are the ALK/ROS1 inhibitor lorlatinib, the JAK2/FLT3 inhibitor pacritinib, the multitargeted tyrosine kinase inhibitor JNJ 26483327, the pan-CDK/JAK2/FLT3 inhibitor zotiraciclib (SB1317/TG02), and the ROS1/TRKA-C/ALK inhibitor reprotrectinib. The remaining three oral compounds, sirolimus (also known as rapamycin), everolimus, and the sirolimus prodrug, temsirolimus, are Type III inhibitors that are "beyond Rule-of-5" natural Table . Oral and non-oral macrocyclic drugs and clinical candidates that target kinases.