BCL-2 Inhibitor

LOXO-338

BCL-2 Inhibitor

Perini GF, et al1; Roberts AW2; Czabotar PE, et al3

Target
B-cell lymphoma 2 (BCL-2) protein is the namesake member of the apoptosis-regulating BCL-2 family. BCL-2 family proteins are key regulators of apoptosis, which is vital for proper tissue development and cellular homeostasis.1-3 Apoptosis can occur via activation of two different pathways: the extrinsic pathway, triggered by a death ligand binding to a death receptor, such as TNF-α to TNFR13; and the intrinsic pathway, regulated by BCL-2 family proteins and their complex protein-protein interactions.1,2 BCL-2 family proteins are functionally classified as either antiapoptotic, such as BCL-2, BCL-xL, and MCL-1, or proapoptotic, including BID, BIM, BAD, BAK, and BAX.1-3

Antiapoptotic BCL-2 family members are often found to be variably upregulated in many types of human cancers, such as different subtypes of B-cell lymphoma and solid tumors, and are frequently correlated with decreased susceptibility to chemotherapeutics and increased radioresistance.1 Overexpression of BCL-2 proteins may be an independent indicator of poor prognosis in malignancies including B-cell lymphomas and some solid tumors.1
Molecule
LOXO-338 is a novel, orally bioavailable small molecule inhibitor of BCL-2, developed to avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition while also maintaining selectivity over MCL-1. In preclinical studies, LOXO-338 selectively inhibited BCL-2 dependent cell lines with limited toxicities in vivo.
Clinical Development
LOXO-338 is being investigated in an open-label, multicenter, phase 1 study in patients with advanced hematologic malignancies who have received standard therapy.

References

  1. Perini GF, et al. J Hematol Oncol. 2018;11(1):65.
  2. Roberts AW. Hematology Am Soc Hematol Educ Program. 2020;2020(1):1-9.
  3. Czabotar PE, et al. Nat Rev Mol Cell Biol. 2014;15(1):49-63.
Clinical Development
LOXO-338 is being investigated in an open-label, multicenter, phase 1 study in patients with advanced hematologic malignancies who have received standard therapy.

References

  1. Perini GF, et al. J Hematol Oncol. 2018;11(1):65.
  2. Roberts AW. Hematology Am Soc Hematol Educ Program. 2020;2020(1):1-9.
  3. Czabotar PE, et al. Nat Rev Mol Cell Biol. 2014;15(1):49-63.

The safety and efficacy of the agents under investigation have not been established. There is no guarantee that the agents will receive regulatory approval and become commercially available for the uses being investigated.

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