Pirtobrutinib (LOXO-305)

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Mechanism of action

From the NCI Drug Dictionary: An orally available, selective, non-covalent Bruton’s tyrosine kinase (BTK) inhibitor with potential antineoplastic activity. Upon oral administration, BTK inhibitor LOXO-305 selectively and reversibly binds to BTK. This prevents both the activation of the B-cell antigen receptor (BCR) signaling pathway and BTK-mediated activation of downstream survival pathways, thereby inhibiting the growth of malignant B cells that overexpress BTK. Reversible binding of LOXO-305 may preserve antitumor activity in the presence of certain acquired resistance mutations, including C481 mutated BTK, and limit toxicity associated with inhibition of other non-BTK kinases.

Preliminary data

  1. BRUIN: link to original article NCT03740529

Mechanisms of resistance

  1. Wang E, Mi X, Thompson MC, Montoya S, Notti RQ, Afaghani J, Durham BH, Penson A, Witkowski MT, Lu SX, Bourcier J, Hogg SJ, Erickson C, Cui D, Cho H, Singer M, Totiger TM, Chaudhry S, Geyer M, Alencar A, Linley AJ, Palomba ML, Coombs CC, Park JH, Zelenetz A, Roeker L, Rosendahl M, Tsai DE, Ebata K, Brandhuber B, Hyman DM, Aifantis I, Mato A, Taylor J, Abdel-Wahab O. Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors. N Engl J Med. 2022 Feb 24;386(8):735-743. link to original article PubMed