A key hallmark of cancer is the ability to manipulate homeostatic pathways within cells to promote tumor growth. A significant example of this is intrinsic apoptotic pathway, which is regulated by members of the B-cell lymphoma 2 (BCL-2) protein family, that comprises two sub-populations of anti-apoptotic proteins (i.e. BCL-2, MCL-1, BCL-xL, BFL-1 and BCL-w) and pro-apoptotic proteins (which are further divided into BH3-only proteins, such as BIM and PUMA, and effector proteins, e.g. BAK and BAX). Under normal conditions, these proteins exist in similar ratios, interacting with one another via an a-helical BH3 “death” domain on the pro-apoptotic protein and a conserved BH3-binding groove on the surface of the anti-apoptotic proteins. In this state of affairs, homodimerization of the effector proteins is not possible, and apoptosis is prevented. However, when stress occurs in the cell, pro-apoptotic proteins are upregulated. This shift further activates BAK and BAX causing apoptosis. In BCL-2-dependent cancers, one or several of the anti-apoptotic BCL-2 proteins are overexpressed resulting in the sequestration and neutralization of pro-apoptotic proteins bound, disabling the ability to induce apoptosis. Inhibitors seeking to restore apoptotic function are designed to target the BH3 binding groove by mimicking the BH3 “death” domain. These inhibitors, dubbed “BH3 mimetics”, function by masquerading as pro-apoptotic BCL-2 proteins, which themselves become bound by the anti-apoptotic proteins thereby releasing the bona fide pro-apoptotic proteins, and restoring apoptosis in cancerous cells. A breakthrough utilizing BH3 mimicry came with the development of the BCL-2 selective inhibitor venetoclax (VEN). Gaining FDA approval in 2016 for patients with chronic lymphocytic leukemia (CLL), and then later for acute myeloid leukemia (AML), VEN has cemented itself as the current standard-of-care drug for treating these diseases. Unfortunately, patients administered VEN develop resistance to the therapeutic after ~17 months of treatment. While these resistances can manifest in multiple ways, the focus of this dissertation was to tackle the compensatory upregulations of sister anti-apoptotic BCL-2 proteins, particularly BCL-xL, MCL-1, and BFL-1. However, targeting these sister anti-apoptotic proteins presents their own challenges. Direct inhibition of BCL-xL causes thrombocytopenia, while multiple clinical trials for MCL-1 inhibitors have been halted or terminated due to cardiotoxicity, leading to the deaths of at least two patients. It has been stated that BFL-1 is the underdog of the BCL-2 family, having received comparatively far less attention than its sister proteins towards the discovery of new anti-cancer drugs. Although herein we have not identified any potent BFL-1 inhibitors, we anticipate our foundational work will provide a springboard for future work.