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a1331852

Properties1
aliasesA 1331852, A1331852, A-1331852, ABT-xL-selective

13 min read

A-1331852

A research-grade, highly selective small-molecule inhibitor of bcl-xl (BCL-XL). Discovered at AbbVie through structure-guided medicinal chemistry as part of the BCL-2 family inhibitor program that also produced navitoclax. Unlike navitoclax (which inhibits BCL-2/xL/w with roughly comparable potency), A-1331852 achieves >1,000-fold selectivity for BCL-xL over BCL-2, making it a precision tool for dissecting cell-survival dependencies — and a potent senolytic in cell types where BCL-xL is a component of the senescent-cell anti-apoptotic pathway (SCAP).

A-1331852 is not approved for clinical use. On-target thrombocytopenia (BCL-xL is essential for platelet survival) limits therapeutic translation and has driven the development of BCL-xL-targeting PROTACs such as DT2216 that spare platelets by exploiting tissue-selective E3 ligase expression.

Identity

FieldValue
PubChem CID71565985
InChIKeyQCQQONWEDCOTBV-UHFFFAOYSA-N
ChEMBL IDCHEMBL3793424
CAS1430844-80-6
Molecular formulaC38H38N6O3S
Molecular weight658.8 g/mol
Key structural motifsadamantane group; benzothiazole moiety; pyrazole ring; isoquinoline core
ClassBH3-mimetic; small-molecule protein-protein interaction inhibitor

ChEMBL ID confirmed: CHEMBL3793424 is correct (molecular formula C38H38N6O3S, MW 658.83 g/mol match verified against ChEMBL API). The alternative ID CHEMBL3753332 is a potassium polysulfide compound — definitively not A-1331852.

Discovery and chemistry

A-1331852 was discovered as part of a structure-guided rescaffolding program at Genentech and AbbVie aimed at improving BCL-xL selectivity over earlier compounds. Koehler et al. 2014 1 describes the SAR programme that replaced a hydrolytically labile hydrazone linker with stable amide/urea scaffolds and then exploited the lipophilic P4 pocket of BCL-xL to drive BCL-xL selectivity. The final compound reported in that paper (compound 22) has a BCL-xL SPR Kd <5 nM and a BCL-w Kd of 62 nM. A-1331852 itself is not identified by name or compound number in Koehler 2014 — the paper describes the SAR framework leading toward this compound class. The Ki values commonly attributed to A-1331852 originate from later AbbVie publications in the same series; Koehler 2014 alone does not source them. needs-replication — primary citation for the specific A-1331852 Ki values (BCL-xL ~10 pM, etc.) not confirmed to a specific PDF in archive; treat as reported but unarchived.

A sister compound, A-1155463, was reported in the same publication series with very similar BCL-xL selectivity but a distinct scaffold.

Target binding profile

Important sourcing note: The Ki values commonly cited for A-1331852 (BCL-xL ~10 pM, BCL-2 ~6 nM, BCL-w ~95 nM, MCL-1 >440 nM) do not appear in the Koehler 2014 PDF verified here. Koehler 2014 reports IC50 (AlphaScreen) and SPR Kd values for its scaffold series (compounds 13, 14, 22) but does not identify A-1331852 specifically. These Ki values likely originate from later publications in the same AbbVie programme (e.g., Souers et al., Leverson et al.) that are not yet fully verified in archive. The values below are retained as widely reported in the literature but are tagged pending source confirmation.

TargetKi (reported)Selectivity vs BCL-xLSource status
BCL-xL~10 pMreference (1×)needs-replication — source PDF not confirmed
BCL-2~6 nM~600× weakerneeds-replication — source PDF not confirmed
BCL-w~95 nM~9,500× weakerneeds-replication — source PDF not confirmed
MCL-1>440 nM>44,000× weakerneeds-replication — source PDF not confirmed
A1/BCL2A1not reported——

The >1,000-fold selectivity window over BCL-2 and MCL-1 is consistently reported across the BCL-xL inhibitor literature and distinguishes A-1331852 from navitoclax. This selectivity makes A-1331852 a key pharmacological tool for attributing senolytic effects specifically to BCL-xL inhibition. needs-replication — Ki values from a single unarchived publication; independent biochemical validation not yet confirmed here.

Mechanism of action

A-1331852 is a BH3-mimetic: it occupies the BH3-binding groove on the BCL-xL surface, displacing pro-apoptotic BH3-only proteins (such as bim, bad, bid) that are sequestered there. Releasing these proteins shifts the balance toward BAX/BAK activation, MOMP, cytochrome c release, and caspase activation. no-fulltext-access — BH3-mimetic mechanism citation 2 could not be verified against Leverson 2015 PDF (download failed; green OA but no URL resolved). Mechanism is consistent with class-level literature and the Koehler 2014 structural work 1.

In normal proliferating cells, BCL-xL inhibition is tolerated unless the cell is primed for apoptosis (i.e., has significant unsequestered BIM or other direct activators). Senescent cells are selectively vulnerable because they upregulate anti-apoptotic BCL-family members — BCL-xL, BCL-W, and BCL-2 — to survive 3. This is the mechanistic basis of the senolytic window. Note: Yosef 2016 4 demonstrated this using ABT-737 (not A-1331852) in IMR90 human fibroblasts and in vivo mouse models; Zhu 2016 5 demonstrated navitoclax (ABT-263) senolysis in HUVECs, IMR90, and MEFs. A-1331852-specific senolytic mechanism data comes from the same biological rationale but has not been independently confirmed in a separate PDF verified here.

Senolytic activity

Cell-type efficacy

Attribution correction: The original draft attributed A-1331852 senolytic activity to Zhu 2016 and Yosef 2016. Both attributions are wrong:

  • Zhu 2016 5 tested navitoclax (ABT-263), not A-1331852. All HUVEC, IMR90, MEF, and preadipocyte senolytic data in that paper are for navitoclax.
  • Yosef 2016 4 tested ABT-737, not A-1331852 or navitoclax. In vivo mouse data (lung, skin) are for ABT-737.

The cell-type-specific BCL-xL SCAP landscape established by these papers applies by extension to A-1331852 (which shares the BCL-xL target), but A-1331852 has not been directly tested in its own published senolytic study in the currently archived literature.

Cell typeSenescent?BCL-xL inhibition senolytic?Agent tested in sourceDominant SCAP
HUVECs (human umbilical vein ECs)YesYesNavitoclax 5; ABT-737 4BCL-xL primary
IMR90 (human lung fibroblasts)YesYes (triple BCL-2+xL+w required)Navitoclax 5; ABT-737 4BCL-2 + BCL-xL + BCL-w triple
Human preadipocytesYesNo / minimalNavitoclax 5Not BCL-2 family
MEFs (murine embryonic fibroblasts)YesYesNavitoclax 5BCL-xL/BCL-2

In IMR90 cells, Zhu 2016 showed that siRNA knockdown of BCL-2, BCL-xL, and BCL-w together (reflecting navitoclax’s triple target profile) was required for senolysis, while BCL-xL siRNA alone was not sufficient 5. Yosef 2016 showed that combined BCL-W + BCL-xL siRNA knockdown reduced DIS cell viability by ~53% in IMR90, comparable to ABT-737 treatment 4. A-1331852’s relatively weak BCL-w activity means it may not fully replicate the triple blockade — but this is inferred from the target profile, not from a direct A-1331852 senolytic experiment. needs-replication — direct A-1331852 senolytic data in any cell type not confirmed to an archived PDF.

The preadipocyte null result is mechanistically important: Zhu 2016 showed navitoclax had no senolytic activity in primary human preadipocytes, consistent with BCL-xL siRNA also being non-senolytic there 5. This indicates BCL-2 family members are not the dominant SCAP in preadipocytes and that A-1331852 would also be expected to be non-senolytic in this cell type.

DimensionStatus
Pathway conserved in humans?yes — BCL-xL senolytic mechanism described in human cell lines
Phenotype conserved in humans?partial — human cell lines (HUVECs, IMR90), not yet in vivo human
Replicated in humans?no — no human in vivo data

López 2025 — first directly-tested A-1331852 senolytic data across TIS phenotypes

Important update (2026-05-08 recency refresh): López et al. 2025 (Cell Death Discov 11:91) provides the first directly-archived characterization of A-1331852 senolytic activity across multiple therapy-induced-senescence (TIS) phenotypes 6. Replicative, mitotic, oxidative, and genotoxic TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. BH3 profiling — measuring mitochondrial priming and BCL-2 family dependencies — was used to map TIS apoptotic landscapes.

Key findings:

  • TIS cells are NOT uniformly more “primed” for apoptosis than their proliferative counterparts — the historical assumption that senescent cells are universally apoptosis-primed is too coarse.
  • BCL-xL dependency IS conserved across TIS phenotypes when sensitizing peptides are used to map BCL-2-family dependencies — competent TIS cancer cells share a BCL-xL dependency regardless of senescence-inducing therapeutic, transient/stable acquisition, or genetic context.
  • A-1331852 (BCL-xL-selective) is senolytic across all tested TIS phenotypes — the first study in archive to directly test A-1331852 (rather than ABT-737 or navitoclax) in a senolytic context with broad TIS-phenotype characterization.

This addresses the prior needs-replication on A-1331852-specific senolytic data: LĂłpez 2025 establishes BCL-xL as a conserved anti-apoptotic effector of the TIS BCL-2/BH3 interactome and demonstrates A-1331852 senolytic activity directly. Caveat: the experimental system is cancer-cell TIS (palbociclib-induced and similar), not normal-tissue replicative or oncogene-induced senescence; extension to natural-aging senescent cells in vivo remains untested with A-1331852.

Selectivity advantage over navitoclax

Compared to navitoclax:

  • Reduced BCL-2 activity (~600-fold): BCL-2 inhibition is associated with neutropenia; A-1331852 largely avoids this.
  • Reduced MCL-1 activity (>44,000-fold): MCL-1 inhibition drives apoptosis in hepatocytes and cardiomyocytes; A-1331852 has minimal MCL-1 engagement.
  • Preserved on-target BCL-xL pharmacology: cancer cell lines dependent on BCL-xL are vulnerable to A-1331852. 2 no-fulltext-access — Leverson 2015 PDF unavailable; claim retained as consistent with class pharmacology but unverified against source.
  • Persistent thrombocytopenia risk: BCL-xL is essential for platelet survival regardless of BCL-2 selectivity — direct BCL-xL inhibitors cause dose-dependent thrombocytopenia. 2 no-fulltext-access — quantitative thrombocytopenia data from Leverson 2015 not verified.

This profile positions A-1331852 as a cleaner mechanistic tool than navitoclax for BCL-xL-specific biology, while not solving the platelet toxicity problem.

Platelet toxicity and clinical translatability

BCL-xL is the dominant survival factor in platelets (megakaryocyte-derived anucleate cells). Unlike nucleated cells that can upregulate BCL-2 family members in response to stress, platelets lack transcriptional capacity and rely constitutively on BCL-xL to delay their 8–10 day lifespan. The role of BCL-xL in platelet survival is established in the literature 1. A-1331852 causes on-target thrombocytopenia at doses overlapping with its therapeutic window — this is an intrinsic consequence of BCL-xL inhibition. 2 no-fulltext-access — quantitative thrombocytopenia data from Leverson 2015 not verified against source PDF.

This is an intrinsic liability of any direct BCL-xL inhibitor, including navitoclax and A-1331852, and is distinct from off-target toxicities. It represents the primary barrier to clinical translation for this compound class.

long-term-unknown — No long-term in vivo senolytic dosing studies with A-1331852 have been published; preclinical use has been acute and/or short-term.

PROTAC derivatives (next-generation context)

BCL-xL-targeting PROTACs have been developed that degrade rather than inhibit BCL-xL, thereby reducing platelet toxicity by exploiting tissue-selective E3 ligase expression:

  • DT2216 — A BCL-xL PROTAC using the BCL-2/BCL-xL binding moiety derived from navitoclax (ABT263) linked to a VHL E3 ligase recruiter 7. Note: Khan 2019 explicitly states the warhead is derived from ABT263, not A-1331852. VHL is poorly expressed in platelets (confirmed by RNA-seq and immunoblot in Khan 2019), so DT2216 degrades BCL-xL in MOLT-4 T-ALL cells (DC50 = 63 nM, Dmax = 90.8%) but has no significant effect on platelet BCL-xL levels at up to 3 µM 7. Demonstrated antitumor activity with reduced thrombocytopenia in xenograft models. needs-human-replication — all data are preclinical; no human senolytic data.
  • PZ15227 — An alternative BCL-xL PROTAC using a CRBN (cereblon) E3 recruiter. unsourced — PZ15227 citation not confirmed via archive; include with caution. This PROTAC approach is mentioned in Khan 2019 as conceptually similar (Extended Data Fig. 4g confirms a cereblon-recruiting BCL-xL PROTAC also degrades BCL-xL but not BCL-2) 7.

The PROTAC strategy illustrates how BCL-xL pharmacology can be exploited for tissue-selective degradation. A-1331852’s own role as a PROTAC warhead is not established in the verified literature — DT2216 uses the navitoclax pharmacophore.

Classification

  • SENS strategy: ApoptoSENS — senolytic targeting senescent cells
  • Hallmark target: cellular-senescence
  • Intervention context: senolytics — BCL-2 family inhibitor class
  • Related compounds: navitoclax (dual BCL-2/xL/w inhibitor; parent class), a1155463 (sister selective BCL-xL compound)
  • Clinical category: research-grade tool compound; not approved or in clinical trials

Limitations and gaps

  • Preclinical tool compound only: No IND filing, no clinical pharmacokinetics, no human in vivo dosing data. Use is restricted to cell culture and short-term mouse studies.
  • Thrombocytopenia is an on-target, unavoidable liability for direct BCL-xL inhibitors — shared with navitoclax and all direct BCL-xL inhibitors.
  • A-1331852-specific senolytic data partially addressed (R34 update 2026-05-08): LĂłpez 2025 6 is the first archived study to directly test A-1331852 across multiple therapy-induced-senescence phenotypes via BH3 profiling, identifying BCL-xL as a conserved TIS dependency and confirming A-1331852 senolytic activity. Earlier cell-type-specific data (HUVECs, IMR90, preadipocyte non-senolysis) still derive from navitoclax (Zhu 2016) and ABT-737 (Yosef 2016) experiments. Remaining gap: no in vivo senolytic study with A-1331852 in naturally-aged (non-cancer) animals.
  • IMR90 triple-SCAP requirement: navitoclax senolysis in IMR90 requires simultaneous BCL-2+BCL-xL+BCL-w inhibition (Zhu 2016). A-1331852’s weaker BCL-w activity suggests it may be less effective than navitoclax in IMR90; this has not been directly tested in a verified study.
  • Preadipocyte non-senolysis: the null result (navitoclax, a BCL-xL/BCL-2/BCL-w inhibitor, is non-senolytic in preadipocytes per Zhu 2016) is informative about the SCAP landscape; by extension, A-1331852 would also be expected to be non-senolytic there.
  • Ki values not sourced to a verified PDF: the specific A-1331852 Ki values (BCL-xL ~10 pM, BCL-2 ~6 nM, BCL-w ~95 nM, MCL-1 >440 nM) are not present in the Koehler 2014 PDF. They likely originate from a later AbbVie publication not yet archived. Tag needs-replication.
  • DT2216 warhead correction: DT2216 uses the ABT263/navitoclax pharmacophore, not an A-1331852 warhead. The PROTAC context for A-1331852 specifically is not established in verified literature.
  • Leverson 2015 unverified: PDF download failed (green OA, no URL resolved). Claims citing 2 remain unverified. no-fulltext-access

Footnotes

Footnotes

  1. doi:10.1021/ml500030p · Koehler MFT et al. (ACS Med Chem Lett 2014, 5:662–667) · in-vitro (AlphaScreen IC50 + SPR Kd, purified protein) · SAR rescaffolding paper describing BCL-xL selective scaffold series (compounds 13, 14, 22); A-1331852 not identified by name in this paper · archive: verified PDF at ↩ ↩2 ↩3

  2. doi:10.1126/scitranslmed.aaa4642 · Leverson JD et al. (Sci Transl Med 2015) · in-vivo (mouse xenograft) + in-vitro · model: cancer cell lines + xenograft mouse models · archive: download failed (green OA, no URL resolved) — PDF NOT VERIFIED no-fulltext-access ↩ ↩2 ↩3 ↩4 ↩5

  3. See 4 — BCL-W and BCL-xL upregulation in senescent IMR90 cells confirmed by immunoblot (Fig. 1d); combined knockdown of BCL-W + BCL-xL reduced DIS cell viability by 53% (Fig. 2c), comparable to ABT-737 treatment. ↩

  4. doi:10.1038/ncomms11190 · Yosef R et al. (Nat Commun 2016, 7:11190) · in-vitro + in-vivo · model: IMR90 human lung fibroblasts; mice (DNA damage–induced lung senescence; p14ARF-driven skin senescence) · Agent tested: ABT-737, NOT A-1331852 or navitoclax · archive: verified PDF at ↩ ↩2 ↩3 ↩4 ↩5 ↩6

  5. doi:10.1111/acel.12445 · Zhu Y, Tchkonia T et al. (Aging Cell 2016, 15:428–435) · in-vitro · model: HUVECs, IMR90, MEFs, human preadipocytes · Agent tested: navitoclax (ABT-263), NOT A-1331852 · archive: verified PDF at ↩ ↩2 ↩3 ↩4 ↩5 ↩6 ↩7 ↩8

  6. doi:10.1038/s41420-025-02379-y · López J, Llop-Hernández À, Verdura S, Serrano-Hervás E, Martinez-Balibrea E, Bosch-Barrera J, Teixidor E, López-Bonet E, Martin-Castillo B, Sardanyés J, Alarcón T, Lupu R, Cuyàs E, Menendez JA · Cell Death Discov 2025 Mar 7;11(1):91 · in-vitro · model: p16-null/p53-proficient, BAX-deficient, BRCA1-mutant cancer cells under replicative, mitotic, oxidative, and genotoxic TIS induced by palbociclib, alisertib, doxorubicin, bleomycin, olaparib · BH3 profiling identifies BCL-xL as conserved dependency across TIS phenotypes; A-1331852 (BCL-xL-selective) shows variable but significant senolytic response across all tested TIS phenotypes · first archive-confirmed A-1331852-specific senolytic study with broad TIS-phenotype characterization · cancer-cell TIS context, not natural-aging in vivo · abstract-only verification 2026-05-08 — full PDF not end-to-end verified. ↩ ↩2

  7. doi:10.1038/s41591-019-0668-z · Khan S et al. (Nat Med 2019, 25:1938–1947) · in-vitro + in-vivo (mouse xenograft) · model: MOLT-4 T-ALL + multiple BCL-xL-dependent cancer lines + mouse xenografts · DT2216 uses ABT263/navitoclax BCL-2/BCL-xL binding moiety as warhead (not A-1331852); VHL E3 ligase recruiter; DC50 = 63 nM, Dmax = 90.8% in MOLT-4; platelet BCL-xL unaffected at ≤3 µM · archive: verified PDF at ↩ ↩2 ↩3

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