ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

Abstract

Overexpression of the prosurvival Bcl-2 family members (Bcl-2, Bcl-xL, and Mcl-1) is commonly associated with tumor maintenance, progression, and chemoresistance. We previously reported the discovery of ABT-737, a potent, smallmolecule Bcl-2 family protein inhibitor. A major limitation of ABT-737 is that it is not orally bioavailable, which would limit chronic single agent therapy and flexibility to dose in combination regimens. Here we report the biological properties of ABT-263, a potent, orally bioavailable Bad-like BH3 mimetic (K i 's of <1 nmol/L for Bcl-2, Bcl-xL, and Bcl-w). The oral bioavailability of ABT-263 in preclinical animal models is 20% to 50%, depending on formulation. ABT-263 disrupts Bcl-2/Bcl-xL interactions with pro-death proteins (e.g., Bim), leading to the initiation of apoptosis within 2 hours posttreatment. In human tumor cells, ABT-263 induces Bax translocation, cytochrome c release, and subsequent apoptosis. Oral administration of ABT-263 alone induces complete tumor regressions in xenograft models of small-cell lung cancer and acute lymphoblastic leukemia. In xenograft models of aggressive B-cell lymphoma and multiple myeloma where ABT-263 exhibits modest or no single agent activity, it significantly enhances the efficacy of clinically relevant therapeutic regimens. These data provide the rationale for clinical trials evaluating ABT-263 in small-cell lung cancer and B-cell malignancies. The oral efficacy of ABT-263 should provide dosing flexibility to maximize clinical utility both as a single agent and in combination regimens. [Cancer Res 2008;68(9):3421-8]

Identification of a novel senolytic agent, navitoclax, targeting the Bcl‐2 family of anti‐apoptotic factors

“…Consistent with this, we previously found imatinib is not senolytic in preadipocytes despite resembling D structurally, targeting many of the same tyrosine kinases, and having similar clinical indications (Modugno, 2014; Zhu et al ., 2015). Additionally, N can cause bleeding by affecting platelets and can cause neutropenia, while newer congeners may have less of these effects (Tse et al ., 2008; Souers et al ., 2013), further emphasizing a need for medicinal chemical optimization. We caution that people should not take N and physicians should not prescribe it for its senolytic effects unless clinical trials show N is effective and safe for these indications.…”

The BCL-2 protein family, BH3-mimetics and cancer therapy

“…16 ABT-737 and its clinical analogue ABT-263 (navitoclax) exemplify this new therapeutic class, with the latter compound currently in phase 2 clinical trials. 161,162 Both compounds bind to BCL-2, BCL-XL and BCL-W (but not to MCL-1 or A1) displacing the endogenous BH3-only proteins, which can then bind to MCL-1, A1 and some of them also to BAX/BAK. This causes killing of tumour cells via a BAX/BAK-dependent mechanism.…”

“…This causes killing of tumour cells via a BAX/BAK-dependent mechanism. 162 Figure 2 Many anticancer agents mediate tumour cell killing though activation of the BCL-2-regulated apoptotic pathway. BH3-only proteins are activated transcriptionally and/or posttranscriptionally in a cytotoxic stimulus-specific manner by many anticancer agents, often with 2-3 members cooperating to induce apoptosis.…”

Stabilization of protein–protein interactions by small molecules

“…However, in the vast majority of cases, PPI modulation is exclusively recognized as inhibition, understandably motivated by a number of wonderful success stories that have been published in recent years. Of these, two of the most prominent examples are the nutlins developed by Roche [4,5], which inhibit the negative regulation of the tumor suppressor p53 by the ubiquitin ligase mouse double minute 2 homolog (MDM2), and navitoclax from Abbott (ABT263), which disrupts the interaction of the antiapoptotic protein Bcl-2 and apoptosis-executing proteins like Bad, Bid and Bak [6][7][8]. Further prominent examples are molecules that inhibit the interaction of human leukemia-derived growth factor (LDGF) with HIV integrase [9], disrupt the binding of KRas and phosphodiesterase (PDE)d [10], transform an active tumor necrosis factor (TNF)a trimer into an inactive dimer [11] or inhibit the binding of PPI modules like the clathrin terminal domain (CTD), or bromodomains with their partners [12,13].…”