Definition

An orally bioavailable combination of DTRMWXHS-12, a Bruton’s tyrosine kinase (BTK) inhibitor, everolimus, a mammalian Target of Rapamycin (mTOR) inhibitor, and pomalidomide, an immunomodulatory drug (IMiD), that may be used for the treatment of B-cell malignancies. Upon oral administration of DTRM-555, the DTRMWXHS-12 component inhibits the activity of BTK and prevents the activation of the B-cell antigen receptor (BCR) signaling pathway. This prevents both B-cell activation and BTK-mediated activation of downstream survival pathways, and leads to an inhibition of the growth of malignant B cells that overexpress BTK. BTK plays an important role in the development, activation, signaling, proliferation and survival of B lymphocytes. The everolimus component binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate a complex that binds to and inhibits the activation of mTOR, a key regulatory kinase. Upregulated in some tumors, mTOR is a serine/threonine kinase involved in regulating cellular proliferation, motility, and survival that is located downstream of the PI3K/Akt signaling pathway. The pomalidomide component may inhibit TNF-alpha production, enhance the activity of T cells and natural killer (NK) cells and enhance antibody-dependent cellular cytotoxicity (ADCC). In addition, pomalidomide may inhibit tumor angiogenesis, promote cell cycle arrest in susceptible tumor cell populations, and stimulate erythropoiesis. The combination of a BTK inhibitor, an mTOR inhibitor and an IMiD may work synergistically to kill malignant B-cells and prevent drug resistance.