Small-molecule inhibitors of protein geranylgeranyltransferase type I

Abstract

Small molecules that inhibit the geranylgeranylation of K-Ras4B and RhoA by protein geranylgeranyltransferase type I (GGTase-I) were identified from chemical genetic screens of heterocycles synthesized through phosphine catalysis of allenes. To further improve the efficacy of the GGTase-I inhibitors (GGTIs), 4288 related compounds bearing core dihydropyrrole/pyrrolidine and tetrahydropyrdine/piperidine scaffolds were synthesized on SynPhase Lanterns in a split-pool manner through phosphine-catalyzed [3+2] and [4+2] annulations of resin-bound allenoates. Testing of the 4288 analogs resulted in several GGTIs exhibiting submicromolar IC₅₀ values. Because proteins such as Ras and Rho GTPases are implicated in oncogenesis and metastasis, these GGTIs might ultimately lead to the development of novel antitumor therapeutics.