INCB160058

INCB160058 is a first-in-class, orally bioavailable small molecule designed to selectively inhibit the JAK2V617F mutant pseudokinase (JH2) domain while sparing wild-type JAK2 activity. It binds with picomolar affinity to the ATP-binding site of the JH2 domain of JAK2V617F, disrupting its function and leading to selective elimination of mutant cells. This mechanism offers a novel approach compared to currently approved JAK inhibitors that target the active kinase (JH1) domain and affect both mutant and wild-type forms. Preclinical studies have shown that INCB160058 reduces pathogenic phospho-STAT5 levels, decreases abnormal megakaryopoiesis, suppresses colony formation in mutant cells, and can eradicate mutant clones with minimal impact on normal hematopoietic cells. The drug is being developed primarily for myeloproliferative neoplasms (MPNs), especially myelofibrosis patients harboring the JAK2V617F mutation[1][4][5][6][8].