ABT-199

ABT-199, developed through a structure-based reverse engineering process, is a novel and specific inhibitor of B-cell lymphoma/leukemia 2 (BCL-2) maintaining a sub-nanomolar affinity towards BCL-2 and over three orders of magnitude less affinity towards BCL-XL. It kills a diverse array of non-Hodgkin lymphoma (NHL) and acute myelogenous leukemia cell lines as well as BCL-2 dependent but not BCL-XL dependent cells via suppressing mitochondrial pathway of apoptosis, exhibiting potent antitumor activity against a wide variety of hematologic malignancies while sparing platelets. According to previous studies, ABT-199 is capable of suppressing tumor growth in several human hematologic tumor xenograft models.

Reference

Matthew S. Davids and Anthony Letai. ABT-199: a new hope for selective BCL-2 inhibition. Cancer Cell 2013; 23(2): 139-141

Synergistic anti-leukemic interactions between ABT-199 and panobinostat in acute myeloid leukemia ex vivo.[Pubmed:27725868]

Am J Transl Res. 2016 Sep 15;8(9):3893-3902. eCollection 2016.

Cure rates for acute myeloid leukemia (AML) remain suboptimal; thus new treatment strategies are needed for this deadly disease. Poor clinical outcomes have been associated with overexpression of the anti-apoptotic Bcl-2 family proteins Bcl-2, Bcl-xL, and Mcl-1, which have garnered great interest as therapeutic targets. While the Bcl-2-selective inhibitor ABT-199 has demonstrated promising preclinical anti-leukemic activities, intrinsic drug resistance remains a problem. In our most recent study, we identified Mcl-1 sequestration of Bim as a mechanism of intrinsic resistance to ABT-199 in AML cells, thus upregulating Bim could overcome such resistance. Histone deacetylase (HDAC) inhibitors (HDACI) are a class of agents that have been confirmed to upregulate Bim. This prompted our hypothesis that combining an HDACI with ABT-199 would overcome intrinsic resistance to ABT-199 and result in synergistic anti-leukemic activity against AML. In this study, we investigated the anti-leukemic activity of panobinostat, a pan-HDACI, in combination with ABT-199 in AML cell lines and primary patient samples. We found that the combined drug treatment resulted in synergistic induction of cell death in both AML cell lines and primary patient samples. Panobinostat treatment resulted in upregulation of Bim, which remained elevated in the presence of ABT-199. In addition, shRNA knockdown of Bim in AML cell lines significantly attenuated apoptosis induced by combined panobinostat and ABT-199. Our results provide compelling evidence that Bim plays a key role in the combined anti-leukemic activity of panobinostat and ABT-199 against AML, and support clinical evaluation of combined panobinostat and ABT-199 in the treatment of AML.

The potential of venetoclax (ABT-199) in chronic lymphocytic leukemia.[Pubmed:27695617]

Ther Adv Hematol. 2016 Oct;7(5):270-287.

Venetoclax (VEN, ABT-199/GDC-0199) is an orally bioavailable BH3-mimetic that specifically inhibits the anti-apoptotic B-cell lymphoma/leukemia 2 (BCL2) protein. Although BCL2 overexpression is not genetically driven in chronic lymphocytic leukemia (CLL), it is nearly universal and represents a highly important and prevalent mechanism of apoptosis evasion, making it an attractive therapeutic target. This review summarizes the role of BCL2 in CLL pathogenesis, the development path targeting its inhibition prior to VEN, and the preclinical and clinical data regarding the effectiveness and safety of VEN. We further strive to contextualize VEN in the current CLL treatment landscape and discuss potential mechanisms of resistance.

Antitumor action of CDK inhibitor LS-007 as a single agent and in combination with ABT-199 against human acute leukemia cells.[Pubmed:27569395]

Acta Pharmacol Sin. 2016 Nov;37(11):1481-1489.

AIM: LS-007 is a CDK inhibitor, which exhibits potent antitumor activity against chronic lymphocytic leukemia and ovarian cancer cells. In this study, we further evaluated the antitumor activity of LS-007 alone and in combination with a Bcl-2 inhibitor ABT-199 in acute leukemia (AL) cells. METHODS: Cell viability was detected using resazurin assay, and cell apoptosis was examined using Annexin V/PI double staining and flow cytometry. The inhibition of LS-007 on kinases was evaluated with the mobility shift assay or ELISA. The expression of relevant signaling molecules was assessed using Western blotting and RT-PCR. Primary lymphocytes from patients with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) were separated using Ficoll-Paque PLUS. RESULTS: LS-007 inhibited the proliferation of 6 AL cell lines with IC50 values of 100-200 nmol/L, and decreased the survival of ALL and AML patient-derived lymphocytes with mean LD50 value of 67 and 102 nmol/L, respectively. In kinase assays in vitro, LS-007 was more selective for the CDK family, inhibiting CDK2, CDK9, CDK1 and CDK4 at low nanomolar concentrations. In HL-60 and CCRF-CEM cells, LS-007 (0.1-0.4 mumol/L) dose-dependently induced cell apoptosis predominantly through CDK9 inhibition-related dephosphorylation at the ser2 residue of RNA pol II and the corresponding depletion of anti-apoptotic proteins, especially Mcl-1 and XIAP. LS-007 (0.2 and 0.4 mumol/L) also induced cell apoptosis in the patient-derived lymphocytes. In HL-60, CCRF-CEM and Molt-4 cells, combined application of LS-007 with ABT-199 (1 or 2 mumol/L) markedly increased cell apoptosis with a maximal decrease in the XIAP levels as compared with either drug used alone. CONCLUSION: CDK inhibitor LS-007 potently inhibits the established human AL cell lines and primary AL blasts, and it also shows remarkable synergy with Bcl-2 inhibitor ABT-199.

Duvelisib treatment is associated with altered expression of apoptotic regulators that helps in sensitization of chronic lymphocytic leukemia cells to venetoclax (ABT-199).[Pubmed:28017967]

Leukemia. 2017 Sep;31(9):1872-1881.

Duvelisib, an oral dual inhibitor of PI3K-delta and PI3K-gamma, is in phase III trials for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin's lymphoma. In CLL, duvelisib monotherapy is associated with high iwCLL (International Workshop on Chronic Lymphocytic Leukemia) and nodal response rates, but complete remissions are rare. To characterize the molecular effect of duvelisib, we obtained samples from CLL patients on the duvelisib phase I trial. Gene expression studies (RNAseq, Nanostring, Affymetrix array and real-time RT-PCR) demonstrated increased expression of BCL2 along with several BH3-only pro-apoptotic genes. In concert with induction of transcript levels, reverse phase protein arrays and immunoblots confirmed increase at the protein level. The BCL2 inhibitor venetoclax induced greater apoptosis in ex vivo-cultured CLL cells obtained from patients on duvelisib compared with pre-treatment CLL cells from the same patients. In vitro combination of duvelisib and venetoclax resulted in enhanced apoptosis even in CLL cells cultured under conditions that simulate the tumor microenvironment. These data provide a mechanistic rationale for testing the combination of duvelisib and venetoclax in the clinic. Such combination regimen (NCT02640833) is being evaluated for patients with B-cell malignancies including CLL.

Venetoclax (ABT-199; GDC-0199) is a highly potent, selective and orally bioavailable Bcl-2 inhibitor with a Ki of less than 0.01 nM. Venetoclax induces autophagy.

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