https://www.selleckchem.com/products/NVP-AUY922.html Herein we describe the discovery of A-1331852, a first-in-class orally active BCL-XL inhibitor that selectively and potently induces apoptosis in BCL-XL-dependent tumor cells. This molecule was generated by re-engineering our previously reported BCL-XL inhibitor A-1155463 using structure-based drug design. Key design elements included rigidification of the A-1155463 pharmacophore and introduction of sp3-rich moieties capable of generating highly productive interactions within the key P4 pocket of BCL-XL. A-1331852 has since been used as a critical tool molecule for further exploring BCL-2 family protein biology, while also representing an attractive entry into a drug discovery program.Prior to genetic mapping, the majority of drug discovery efforts involved phenotypic screening, wherein compounds were screened in either in vitro or in vivo models thought to mimic the disease state of interest. While never completely abandoning phenotypic approaches, the labor intensive nature of such tests encouraged the pharmaceutical industry to move away from them in favor of target-based drug discovery, which facilitated throughput and allowed for the efficient screening of large numbers of compounds. However, a consequence of reliance on target-based screening was an increased number of failures in clinical trials due to poor correlation between novel mechanistic targets and the actual disease state. As a result, the field has seen a recent resurrection in phenotypic drug discovery approaches. In this work, we highlight some recent phenotypic projects from our industrial past and in our current academic drug discovery environment that have provided encouraging results.Recent years have seen an unprecedented level of innovation in allosteric drug discovery and development, with multiple drug candidates advancing into clinical studies. #link# From early examples of allosteric drugs like GABAA receptor modulators (benzodiazepine