AZD5153

AZD5153 is a bivalent, selective, and orally active BET/BRD4 bromodomain inhibitor with an IC₅₀ of value of 5 nM for full-length BRD4 (FL-BRD4). AZD5153 ligates two bromodomains in BRD4 simultaneously. AZD5153 can be used for the study of cancer, such as acute myeloid leukemia, multiple myeloma, and diffuse large B-cell lymphoma^[1]. In Vitro:AZD5153 demonstrates a remarkable enhancement in potency for the displacement of full-length BRD4 relative to BD1, with IC₅₀ values of 5.0 nM and 1.6 µM, for FL-BRD4 and BD1 domain alone (BD1-BRD4) , respectively. AZD5153 demonstrated a drastically reduced IC₅₀ value of 1.4 µM in displacing mutant BRD4 from chromatin, in contrast to 8.7 nM IC₅₀ for wild-type protein^[1].
AZD5153 (5.4 nM; 16 h) in MM.1S cells reduces MYC protein levels via flow cytometry^[1].
AZD5153 (GI₅₀ <150 nM; 72 h) in 61 hematologic cancer cell lines (AML, MM, DLBCL) inhibits cell growth^[1].
AZD5153 (100 nM; 48 h) in MV-4-11 and MM.1S cells induces significant apoptosis via caspase-3 activation, unlike I-BET762^[1].
AZD5153 (200 nM; 24 h) in hematologic cell lines (AML, MM, DLBCL) modulates MYC, E2F, and mTOR transcriptional programs via RNA-seq. AZD5153 (200 nM; 24 h) in sensitive hematologic cell lines (MOLP8, MV-4-11, OCILY19) downregulates mTOR pathway proteins (p-p70S6K, PRAS40, p-4EBP1) via RPPA and western blot^[1].
In Vivo:AZD5153 (1-5 mg/kg; oral gavage; daily; 14-28 days) in MV-4-11 (AML), KMS11 (MM), KARPAS422 (DLBCL) xenograft mice induces tumor stasis or regression^[1].
AZD5153 (6.4-12.8 mg/kg/week; subcutaneous mini-pump; continuous; 14 days) in MV-4-11 xenograft mice achieves near-complete tumor regression with prolonged BRD4 inhibition^[1].