Introduction

Overexpression of the anti-apoptotic protein BCL-2 is a hallmark of many hematologic malignancies, enabling tumor cells to evade programmed cell death. Building on the success of venetoclax, AbbVie developed Surzetoclax (ABBV-453) - a next-generation, highly potent and selective, orally bioavailable BCL-2 inhibitor (Figure 1).

Surzetoclax binds BCL-2, displacing pro-apoptotic proteins and reactivating the apoptotic pathway in BCL-2–dependent cancer cells [1]. In preclinical studies, it demonstrates sub-nanomolar affinity for BCL-2 and induces apoptosis in sensitive hematologic tumor cell lines (e.g., RS4;11, EC₅₀ = 4.7 nM in 10% human serum) [2]. In xenograft models, including acute lymphoblastic leukemia (ALL) and other BCL-2–driven malignancies, Surzetoclax produced marked tumor growth inhibition compared with other BCL-2 inhibitors [2].

The compound demonstrates favorable pharmacokinetics, dose-dependent target engagement, and was designed to reduce risks of tumor lysis syndrome and other dose-limiting toxicities observed with venetoclax [3]. Currently in Phase 1 clinical evaluation, Surzetoclax represents a promising advance in apoptosis-targeted oncology therapeutics [4] (Figure 1).

***Figure 1. Crystal Structure of BCL-2 with venetoclax (PDB: 6O0K). Chemical structure of Surzetoclax (ABBV-453), a next-generation BCL-2 inhibitor***

BCL-2 and the Survival Advantage in Multiple Myeloma

The BCL-2 family of proteins plays a crucial role in controlling apoptosis - the natural process of programmed cell death. In healthy cells, BCL-2 helps maintain balance between survival and death signals [5]. In many cancers, however, BCL-2 becomes overactive, allowing malignant cells to resist apoptosis and continue growing [6].

One disease where this mechanism is especially important is multiple myeloma (MM). Around 40% of MM patients have specific chromosomal changes called IgH translocations, which can alter the activity of survival genes. The most common t(11;14) translocation is associated with elevated BCL-2 levels in many cases, rendering affected cells relatively more reliant on BCL-2 for survival compared to other MM subtypes [6, 7, 8].

This BCL-2 dependency provides a strong biological rationale for targeted therapy. By inhibiting BCL-2, apoptosis can be re-engaged selectively in malignant plasma cells that rely on this protein for survival. Surzetoclax (ABBV-453), a next-generation BCL-2 inhibitor, was developed to exploit this vulnerability and represents a promising therapeutic approach for patients with t(11;14)-positive multiple myeloma [9, 10].

Next-Generation BCL-2 Inhibitors: The Road to Surzetoclax (ABBV-453)

The development of Surzetoclax (ABBV-453) stems from a decade of structural and mechanistic insights gained from earlier BH3 mimetics. BH3 mimetics are small molecules designed to exploit the dependence of cancer cells on anti-apoptotic BCL-2 family proteins for survival.

The BH3 (BCL-2 homology 3) domain is a short α-helical motif present in pro-apoptotic members of the BCL-2 family such as BIM, BID, and PUMA. This domain enables these proteins to bind to and neutralize anti-apoptotic counterparts like BCL-2, BCL-XL, and MCL-1, tipping the balance toward mitochondrial outer membrane permeabilization and activation of the apoptotic cascade. BH3 mimetics replicate this interaction by occupying the same hydrophobic binding groove on anti-apoptotic proteins, thereby releasing pro-death effectors such as BAX and BAK to restore programmed cell death [11].

From ABT-737 to Venetoclax: Building the Foundation

The first experimental BH3 mimetic, ABT-737, provided proof of concept that pharmacologic inhibition of BCL-2 family proteins could effectively induce apoptosis in both hematologic and solid tumor models [12]. Although ABT-737 showed potent activity, its poor oral bioavailability limited clinical translation. To address this, researchers developed ABT-263 (navitoclax) - an orally bioavailable inhibitor targeting BCL-2, BCL-XL, and BCL-W [13] (Figure 2).

Navitoclax demonstrated strong antitumor effects in B-cell malignancies and small-cell lung cancer, but its use was constrained by dose-limiting thrombocytopenia caused by on-target inhibition of BCL-XL in platelets [14].

***Figure 2. Chemical structures of commonly used BCL-2 inhibitors.***

To overcome the platelet toxicity associated with BCL-XL inhibition, structure-based drug design efforts focused on achieving greater selectivity for BCL-2. This led to the development of ABT-199 (venetoclax), a highly selective and orally bioavailable BCL-2 inhibitor that maintained potent pro-apoptotic activity while sparing platelets [15]. Venetoclax represented a major therapeutic advance, earning regulatory approval for chronic lymphocytic leukemia (CLL) and other hematologic malignancies. Despite its remarkable efficacy in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), venetoclax therapy can cause tumor lysis syndrome (TLS) due to rapid cancer cell death, and resistance may develop in patients with upregulated MCL-1 or BCL-XL expression. These limitations have fueled the search for new BCL-2 inhibitors with improved pharmacologic and safety profiles.

Building on the molecular and clinical lessons from Venetoclax, researchers sought to design next-generation BCL-2 inhibitors with enhanced potency, refined selectivity, and broader antitumor activity. These efforts culminated in the discovery of Surzetoclax (ABBV-453) - a structurally optimized molecule engineered to overcome resistance mechanisms and expand the therapeutic scope of BH3 mimetics across diverse malignancies.

Surzetoclax (ABBV-453): Integrating Medicinal Chemistry Expertise with AI-Guided Retrosynthesis

Surzetoclax (ABBV-453) design reflects a nontrivial feat of medicinal chemistry with its structure built around four key elements (Figure 3):

A 5,6,7-fused tricyclic heteroaromatic system — a 7-azaindole fused with an oxazepane;
A 6,11,6-fused tricyclic system with two stereocenters;
A trans-1,2-disubstituted tetrahydropyran attached to an ortho-nitroaniline; and
An N-sulfonylbenzamide fragment that links all the aforementioned units.

This arrangement produces a conformationally constrained molecule with sub-nanomolar affinity for BCL-2, enhanced selectivity over BCL-XL and MCL-1, favorable pharmacokinetics, and controlled apoptotic induction to reduce tumor lysis syndrome (TLS) risk. The incorporation of macrocyclic elements within the BCL-2 hot-spot binding region adds rigidity, potency, and durable in vivo activity at low doses - but also makes the molecule exceptionally challenging to synthesize.

***Figure 3. Surzetoclax’s structure: key elements***

How AbbVie Built It: The Literature Synthesis

The published synthesis of ABBV-453, described in WO 2023/141536 A1, showcases just how complex this target is. The route proceeds through a 27-step convergent route with a 12-step longest linear sequence (LLS).

a) Building the 6,11,6-Fused Tricycle

Dimedone (A) initiates the sequence. Condensation with paraformaldehyde in the presence of BF₃·Et₂O produces the 1,3-dioxolane (B), which undergoes organometallic addition to yield (C). Conversion of the resulting alcohol to alkyl chloride (D) is achieved via MsCl/TEAC, followed by an (S)-CBS reduction to generate chiral alcohol (E).
Nucleophilic substitution with a Boc-protected piperazine gives (F), which undergoes macrocyclization with the bis-triflate of propane-1,3-diol to close the 11-membered ring, affording (G). Boc-deprotection with TFA produces (H), and an SNAr reaction with an aryl fluoride completes the 6,11,6-fused tricyclic intermediate (I) bearing both stereocenters (Figure 4).

***Figure 4. Building the 6,11,6-Fused Tricycle***

b) Assembly of the Tetrahydropyran Fragment

Racemic (3,4-dihydro-2H-pyran-2-yl)methanol (J) is enzymatically resolved using porcine pancreatic lipase to provide the (S)-alcohol (K) (with 93 % ee). Benzyl protection gives (L), which undergoes hydroboration–oxidation to form secondary alcohol (M). Methylation yields (N), followed by tosylation and subsequent displacement with sodium azide to afford (P). A Staudinger reduction and SNAr reaction with 4-fluoro-3-nitrobenzenesulfonamide furnish the sulfonamide intermediate (Q) - the THP-derived fragment (Figure 5).

***Figure 5. Assembly of the Tetrahydropyran Fragment***

c) Constructing the 5,6,7-Fused Heteroaromatic System and Final Coupling

Starting from 5-bromo-7-azaindole (R), oxidation and chlorination generate the 6-chloro derivative (S). The pyrrole nitrogen is SEM-protected, and SNAr coupling with N-tosylaminopropanol gives (T). Microwave-assisted Cu-mediated cyclization closes the oxazepane ring, yielding (U). Detosylation with sodium naphthalene affords (V), which undergoes Buchwald–Hartwig coupling with tricyclic intermediate (I) to produce (W).
Subsequent SEM-deprotection and saponification give acid (X), which couples with the THP fragment (Q) via EDCI·HCl to form the N-sulfonylamide linkage, completing ABBV-453 (Figure 6).

***Figure 6. Constructing the 5,6,7-Fused Heteroaromatic System and Final Coupling***

Human-Directed Retrosynthesis in ChemAIRS. Exploration of Synthetic Routes to Surzetoclax

Given the molecule’s weight (near 1000 Da), multiple fused tricyclic and macrocyclic ring systems, and a high number of heteroatoms, Surzetoclax (ABBV-453) embodies significant structural complexity, posing a formidable challenge even for seasoned synthetic chemists.

Using ChemAIRS in High-Risk Retrosynthesis mode (calculation depth = 12) demonstrated the platform’s capacity to navigate the formidable structural complexity of ABBV-453. Guided human input transformed the computational suggestions into a practically executable and strategically streamlined route, achieving a more convergent design and improved synthetic logic compared with the published sequence (Figure 7).

***Figure 7. Human-directed synthesis of ABBV-453 in ChemAIRS***

Fragmentation Strategy

The synthesis was deconstructed into three modular components (Figure 7):

Fragment 25a: the 6,11,6-fused tricyclic core;
Fragment 12a: the trans-disubstituted THP;
Fragment 12b: the 5,6,7-fused heteroaromatic tricycle.

a) Fragment 25a – The Core Tricycle

Fragment 25a was elaborated in ten steps beginning from dimedone (15a). Although cyclohexenone (16a) is commercially available, it is prohibitively expensive; therefore, it was manually introduced into the route as a derived intermediate from dimedone, improving both accessibility and scalability.

A Morita–Baylis–Hillman condensation of 16a with formaldehyde provided intermediate (17a), which was converted to the primary alkyl bromide (18a) and subsequently reacted with protected chiral piperazine (18b) to afford (19a). CBS reduction established both stereocenters in the fused tricyclic framework. After TBS removal, macrocyclization with bis(triflate) (22a) yielded the 11-membered intermediate (23b). A Mizoroki–Heck coupling with 1-chloro-4-iodobenzene furnished (24a), and Boc deprotection completed the 6,11,6-fused tricyclic fragment 25a (Figure 8).

***Figure 8. Fragment 25a – The Core Tricycle***

b) Fragment 12a – The THP Motif

Assembled in four steps from building blocks (5a) and (5b). Hydroboration gives alcohol (7a); methylation yields (8a); debenzylation furnishes (9a). A Mitsunobu reaction replaces the azide-introduction sequence from the patent, generating (10a). Staudinger reduction forms amine (11a), which reacts via SNAr with aryl fluoride (11b) to complete fragment 12a (Figure 9).

***Figure 9. Fragment 12a – The THP Motif***

c) Fragment 12b – The Azaindole-Oxazepane Tricycle

SEM protection of 7-azaindole (1b) provides (2b). A nickel-photoredox C–N coupling with 3-aminoprop-1-ol (2a) forms (3a) efficiently without protecting the hydroxyl group [16]. Base-promoted cyclization yields (4b), followed by a Buchwald–Hartwig coupling with trihalobenzene (4a) to deliver fragment 12b (Figure 10).

***Figure 10. Fragment 12b – The Azaindole-Oxazepane Tricycle***

Final Assembly

Fragments 12a and 12b are joined through a Pd-catalyzed amidocarbonylation (Hermann’s catalyst, tBu₃PH·BF₄, Mo(CO)₆) [17] to afford (13a). SEM-deprotection furnishes (25b), which undergoes a final SNAr coupling with (25a) to yield ABBV-453 (Figure 11).

Algorithmic retrosynthesis augments human intuition

The human-directed ChemAIRS synthesis of ABBV-453 represents a strategically optimized and more experimentally practical route compared with the patented sequence. While the overall number of steps is similar, the revised design achieves greater convergence, modularity, and adaptability, translating to improved feasibility for both analog generation and potential scale-up (Table 1).

Table 1. Head-to-Head Comparison: Patent Route vs. Human-Directed AI Route

In practical terms, the ChemAIRS-guided route preserves synthetic integrity while enhancing route design logic and experimental efficiency. Human expertise was key in transforming computational suggestions into a coherent, executable synthesis, demonstrating how AI-assisted retrosynthesis can extend chemists’ strategic reach rather than replace it. The outcome underscores a broader trend - the integration of algorithmic retrosynthesis with human intuition to generate robust, scalable routes for structurally demanding targets like Surzetoclax.

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Integrating Human Insight with AI: Retrosynthetic Exploration of Surzetoclax (ABBV-453)