ABT 199
[CAS# 1257044-40-8]

Identification

• Classification: Biochemical >> Inhibitor >> Apoptosis >> Bcl-2 inhibitor
• Name: ABT 199
• Synonyms: 4-[4-[[2-(4-Chlorophenyl)-4,4-dimethyl-1-cyclohexen-1-yl]methyl]-1-piperazinyl]-N-[[3-nitro-4-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]phenyl]sulfonyl]-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)-benzamide
• Molecular Formula: C₄₅H₅₀ClN₇O₇S
• Molecular Weight: 868.44
• CAS Registry Number: 1257044-40-8
• EC Number: 820-130-9
• SMILES: CC1(CCC(=C(C1)C2=CC=C(C=C2)Cl)CN3CCN(CC3)C4=CC(=C(C=C4)C(=O)NS(=O)(=O)C5=CC(=C(C=C5)NCC6CCOCC6)[N+](=O)[O-])OC7=CN=C8C(=C7)C=CN8)C

Properties

• Density: 1.3±0.1 g/cm³ Calc.^*
• Solubility: 10Mm (DMSO) (Expl.)
• Index of refraction: 1.644 (Calc.)^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07;GHS08 Danger
• Risk Statements: H302-H315-H317-H319-H334-H335-H341-H361-H372-H413
• Safety Statements: P203-P233-P260-P261-P264-P264+P265-P270-P271-P272-P273-P280-P284-P301+P317-P302+P352-P304+P340-P305+P351+P338-P318-P319-P321-P330-P332+P317-P333+P317-P337+P317-P342+P316-P362+P364-P403-P403+P233-P405-P501

Hazard Classification

Hazard	Class	Category Code	Hazard Statement
Reproductive toxicity	Repr.	2	H361
Specific target organ toxicity - repeated exposure	STOT RE	1	H372
Eye irritation	Eye Irrit.	2	H319
Specific target organ toxicity - single exposure	STOT SE	3	H335
Skin irritation	Skin Irrit.	2	H315
Acute toxicity	Acute Tox.	4	H302
Respiratory sensitization	Resp. Sens.	1	H334
Germ cell mutagenicity	Muta.	2	H341
Skin sensitization	Skin Sens.	1	H317
Chronic hazardous to the aquatic environment	Aquatic Chronic	4	H413
Specific target organ toxicity - repeated exposure	STOT RE	2	H373
Eye irritation	Eye Irrit.	2A	H319
Reproductive toxicity	Repr.	1B	H360
Chronic hazardous to the aquatic environment	Aquatic Chronic	1	H410

Discovery and Applications

ABT-199, also known by its generic name venetoclax, is a small-molecule drug that emerged from targeted drug discovery efforts aimed at selectively inhibiting a specific anti-apoptotic protein. The compound is a potent and selective inhibitor of B-cell lymphoma 2 (BCL-2), a key regulator of apoptosis that is frequently overexpressed in certain hematologic malignancies. The design and development of ABT-199 were driven by the need to address limitations associated with earlier BCL-2 inhibitors, such as lack of selectivity and dose-limiting thrombocytopenia.

The discovery of ABT-199 followed extensive structure-based drug design that focused on developing molecules capable of binding the BH3-binding groove of the BCL-2 protein with high affinity, thereby mimicking the action of pro-apoptotic BH3-only proteins. ABT-199 was derived from a predecessor molecule, ABT-263 (navitoclax), which showed efficacy but also inhibited BCL-XL, another anti-apoptotic protein crucial for platelet survival. By eliminating significant binding to BCL-XL while retaining high potency against BCL-2, ABT-199 demonstrated a favorable therapeutic profile with reduced risk of thrombocytopenia.

Preclinical evaluations showed that ABT-199 induces apoptosis in BCL-2-dependent cancer cells and achieves significant tumor regression in animal models of lymphoid malignancies. Its efficacy is particularly pronounced in chronic lymphocytic leukemia (CLL), where BCL-2 overexpression contributes to resistance to conventional chemotherapy. ABT-199 effectively disrupts the interaction between BCL-2 and pro-apoptotic proteins such as BIM, leading to mitochondrial outer membrane permeabilization and activation of the caspase cascade.

ABT-199 progressed into clinical development and demonstrated strong single-agent activity in patients with relapsed or refractory CLL, including those with high-risk cytogenetic abnormalities such as 17p deletion. The compound showed rapid reduction in lymphocyte counts and lymph node volumes in responsive patients. One unique clinical challenge observed during early trials was tumor lysis syndrome (TLS), a potentially life-threatening condition resulting from the rapid killing of large numbers of tumor cells. This led to the implementation of a stepwise dose ramp-up strategy in clinical protocols to mitigate TLS risk.

The compound was later approved under the trade name venetoclax for the treatment of patients with CLL, particularly those with 17p deletion, and its indications have since expanded to include other hematologic malignancies such as acute myeloid leukemia (AML). In AML, venetoclax is commonly used in combination with hypomethylating agents or low-dose cytarabine in patients who are ineligible for intensive chemotherapy. This combination has significantly improved response rates and overall survival in older patients with newly diagnosed AML.

The application of ABT-199 has extended to several ongoing clinical studies in other BCL-2-dependent cancers, including non-Hodgkin lymphoma, multiple myeloma, and some solid tumors. Its utility in combination therapies is of particular interest, where synergistic interactions with other agents, such as kinase inhibitors or DNA-damaging drugs, are being explored. The development of resistance to ABT-199 through various mechanisms, such as upregulation of alternative anti-apoptotic proteins like MCL-1, is an area of active investigation, prompting research into rational combination strategies.

ABT-199 represents a landmark achievement in the field of targeted apoptosis modulation. Its development exemplifies how deep understanding of protein-protein interactions and disease-specific molecular dependencies can lead to the creation of highly selective therapeutics with meaningful clinical benefit. Its success has established a precedent for designing selective inhibitors of apoptosis-regulating proteins and has had a substantial impact on the treatment paradigm for hematologic malignancies.

References

2018. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood, 133(1).
DOI: 10.1182/blood-2018-08-868752

2021. BH3 profiling identifies ruxolitinib as a promising partner for venetoclax to treat T-cell prolymphocytic leukemia. Blood, 137(25).
DOI: 10.1182/blood.2020007303

2024. Erste Daten zu vollständig oralem Regime bei MDS und CML. InFo Hämatologie + Onkologie.
DOI: 10.1007/s15004-024-0506-4