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Targeted protein degradation (TPD) with heterobifunctional small molecules is emerging as a promising new therapeutic modality in oncology. We sought to understand how TPD compares versus targeted protein inhibition. We used BRD4 as a surrogate target given literature showing BET degraders have a global suppressive effect on transcription compared to BET inhibitors that preferentially affect superenhancers. We selected the BET degrader CFT-743 from a library of CRBN-biased degraders based on its specificity, potency and optimum in vivo properties that enable a therapeutic window. While subtle changes in chemistry around CFT-743 had negligible impact on vitro potency, the effect on therapeutic index was significant. In vitro, CFT-743 is more potent than a BET inhibitor (AZD5153) and a CDK9 inhibitor (dinaciclib) in 100% and 97% of 38 leukemia lines tested. In mice bearing HL60 tumors, CFT-743 has similar efficacy as dinaciclib (81% regression versus 99% tumor growth inhibition (TGI)). Pre-dosing mice with the CRBN binding molecule pomalidomide significantly attenuates CFT-743 activity (TGI 40%) rendering the observed efficacy on par with BET inhibitor CPI-203 (TGI 2%) and thus confirming superior efficacy is dependent on BET degradation. In Kasumi1 and THP1 tumor models, CFT-743 efficacy is more like CPI-203 (regressions in Kasumi1 and strong TGI/moderate regressions in THP1) than dinaciclib (moderate regression and 0% TGI). In RS4;11 tumors CFT-743 promotes complete regression whereas dinaciclib and CPI-203 display modest efficacy (80% and 58% TGI). Pharmacokinetic and pharmacodynamic studies in mice bearing MV4;11 tumors demonstrate that a high initial plasma exposure of CFT-743 followed by fast compound clearance is sufficient to drive rapid loss of BRD4 in tumors ( Collectively, these data highlight the in vivo features important for efficacy and tolerability with BET degraders and establish the relationships between degrader pharmacokinetics, target protein degradation and efficacy. Citation Format: Brendon Ladd, David Cocozziello, Mark E. Fitzgerald, Ryan E. Michael, Ellen F. Vieux, Linda Lee, Marta Issa, Jacob D. Feala, Roman V. Agafonov, Eun Sun Park, Christopher G. Nasveschuk, David A. Proia. In vivo profiling of BET degraders establishes optimal pharmacological properties that showcase distinct biological differences from BET inhibitors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1949.