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Preclinical Development Exploring BTK


An investigational, novel, selective, and reversible Bruton's tyrosine kinase (BTK) inhibitor designed to inhibit wild-type and cysteine-481 (C481S)–mutated BTK.

LOXO-305 entered studies in late 2017 and is expected to enter clinical development in 2018, pending Investigational New Drug (IND) approval.

Exploring BTK

About BTK

BTK is a cytoplasmic tyrosine kinase in the B-cell receptor (BCR) pathway.1,2 BTK activation results in downstream signaling that controls nuclear factor-κB, a critical regulator of B-lymphocyte survival.3-6 Use of BTK inhibitors in diseases such as mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), Waldenström’s macroglobulinemia (WM), and marginal zone lymphoma (MZL) has demonstrated clinical benefit, though acquired BTK point mutations such as C481S can cause resistance to these therapies.7-16

  1. Smith CI, Islam KB, Vorechovsky I, Olerup O, Wallin E, Rabbani H, et al. X-linked agammaglobulinemia and other immunoglobulin deficiencies. Immunol Rev. 1994;138:159-183.
  2. Vihinen M, Nilsson L, Smith CI. Tec homology (TH) adjacent to the PH domain. FEBS Lett. 1994;350:263-265.
  3. Bajpai UD, Zhang K, Teutsch M, Sen R, Wortis HH. Bruton's tyrosine kinase links the B cell receptor to nuclear factor kappaB activation. J Exp Med. 2000;191:1735-1744.
  4. Petro JB, Rahman SM, Ballard DW, Khan WN. Bruton's tyrosine kinase is required for activation of IkappaB kinase and nuclear factor kappaB in response to B cell receptor engagement. J Exp Med. 2000;191;1745-1754.
  5. Derudder E, Herzog S, Labi V, Yasuda T, Kochert K, Janz M, et al. Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells. Proc Natl Acad Sci USA. 2016;113:5065-5070.
  6. Yu L, Mohamed AJ, Simonson OE, Vargas L, Blomberg KE, Bjorkstrand B, et al. Proteasome-dependent autoregulation of Bruton tyrosine kinase (Btk) promoter via NF-kappaB. Blood. 2008;111:4617-4626.
  7. Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, et al. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016;387:770-778.
  8. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369:32-42.
  9. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374:323-332.
  10. Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, et al. Ibrutinib in previously treated Waldenstrom's macroglobulinemia. N Engl J Med. 2015;372:1430-1440.
  11. Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton's tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286-2294.
  12. Chiron D, Di Liberto M, Martin P, Huang X, Sharman J, Blecua P. et al. Cell-cycle reprogramming for PI3K inhibition overrides a relapse-specific C481S BTK mutation revealed by longitudinal functional genomics in mantle cell lymphoma. Cancer Discov. 2014;4:1022-1035.
  13. Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352-2354.
  14. Cheng S, Guo A, Lu P, Ma J, Coleman M, Wang YL. Functional characterization of BTK(C481S) mutation that confers ibrutinib resistance: exploration of alternative kinase inhibitors. Leukemia. 2015;29:895-900.
  15. Maddocks KJ, Ruppert AS, Lozanski G, Heerema NA, Zhao W, Abruzzo L, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80-87.
  16. Noy A, Vos SD, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129(16):2224-2232.

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