Bridging Biology and Chemistry: BCL6, BMS-986458, and AI-Predicted Routes to Scalable Degraders
BCL6: Central Role in Germinal Center Biology and a Validated Therapeutic Target in Lymphomas
BCL6 (B-cell lymphoma 6) is a transcriptional repressor that orchestrates germinal center B-cell development by silencing pathways controlling DNA damage response, apoptosis, and cell cycle exit. This regulatory function allows B-cells to proliferate and undergo affinity maturation, a process essential for producing high-affinity antibodies [1 - 5].
Figure 1. Crystal structure of the BCL6 BTB domain dimer (PDB: 1R28). Ribbon diagram representation.
In normal physiology, BCL6 maintains efficient germinal center reactions by restraining premature cell death and differentiation, whereas aberrant expression transforms it into a potent oncogenic driver. Overexpression is strongly linked to diffuse large B-cell lymphoma (DLBCL) as well as other lymphoid malignancies, including follicular and nodular lymphocyte-predominant Hodgkin (NLPHL) lymphomas. In these contexts, BCL6 supports malignant survival programs and contributes to immune evasion. [6 - 9].
Its dual importance in immunity and cancer has validated BCL6 as a therapeutic target, with current strategies focusing not only on small-molecule inhibitors but also on targeted protein degraders to dismantle its oncogenic activity [10 - 16] (Figure 2).
Figure 2. Representative Chemical Structures of BCL6 Inhibitors and Degraders
BMS-986458: A Clinical-Stage BCL6 Degrader
Among BCL6-targeting degraders, BMS‑986458 (developed by Bristol‑Myers Squibb) is the leading BCL6 degrader in clinical development. It is an oral, cereblon-recruiting ligand-directed degrader (LDD) designed to induce selective, ubiquitin-mediated elimination of the BCL6 transcription factor. First structurally disclosed at the ACS Spring 2025 meeting and covered under patent WO2023212147A1, the compound demonstrates potent preclinical activity across diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) [17] (Figure 3).
Figure 3. BMS-986458: oral cereblon-recruiting, ligand-directed BCL6 degrader
In vitro, it rapidly depletes BCL6 in most NHL cell lines and patient-derived xenografts, driving transcriptional changes in cell-cycle and interferon pathways. A key feature is its ability to upregulate CD20, restoring sensitivity to anti-CD20 therapies and yielding strong synergy with rituximab-like antibodies in xenograft models. In vivo, oral dosing produces sustained BCL6 degradation, tumor regression, and prolonged survival, with good tolerability in toxicology studies. Preliminary findings from the ongoing Phase 1/2 trial (NCT06090539) indicate that the drug is well tolerated and shows early signs of efficacy in relapsed/refractory NHL [16].
The Hidden Hurdle: Translating Promising Biology into Scalable Chemistry
While BMS-986458 holds immense therapeutic promise, its journey from lab to clinic depends equally on the ability to manufacture it efficiently and sustainably. More broadly, many complex heterobifunctional PROTAC molecules present synthetic challenges because of their large size, multiple functional groups, and the need to connect two bulky ligands through carefully engineered linkers. These features often lead to long step counts, purification difficulties, and solubility issues, making their synthesis and scale-up more demanding than for conventional small molecules [18-21].
This is where AI-powered retrosynthesis platforms such as ChemAIRS come into play. By predicting alternative synthetic routes, ChemAIRS offers medicinal and process chemists new strategies to overcome bottlenecks, reduce costs, and improve sustainability in drug development.
ChemAIRS and the Synthetic Route to BMS-986458
The patent-disclosed route to BMS-986458 follows a modular assembly strategy and incorporates several palladium-catalyzed transformations, notably Suzuki–Miyaura and Buchwald–Hartwig couplings. In particular, construction of the indazole–piperidine-2,6-dione scaffold 5 relies heavily on Pd catalysis (Figure 4) [17]. These methods are proven but expensive and require significant downstream purification to remove trace Pd. Even in small-scale lab work, this can affect the accuracy of assays and analytical purity. At larger scales, strict regulatory requirements demand robust and often costly purification strategies to ensure safety and quality.
Figure 4. Construction of the indazole–piperidine-2,6-dione motif (as described in WO 2023212147A1)
On the other hand, while the ChemAIRS route mirrors the patent strategy in how it assembles the major molecular fragments, it introduces distinct and potentially more efficient approaches to building the core scaffolds (Figure 5). Alternative strategies were explored with the help of ChemicalAI retrosynthesis software. Using retrosynthetic analysis, the platform identified a palladium-free synthesis of BMS-986458 with the same overall step count. These alternative routes avoid palladium altogether, instead relying on cheaper, water-soluble transition metals and suggesting more economical building blocks.
Fig. 5: Exemplary ChemAIRS-predicted synthetic route to BMS-986458
Among the notable innovations were:
Regioselective zincation of indazole precursors. ChemAIRS proposed regioselective zincation of 6-bromo-3-iodo-1-methyl-1H-indazole (1b), using chemistry developed by Unsinn and Knochel [22], followed by trapping with ethyl bromoacetate (Figure 6). The resulting intermediate (2b) could then be alkylated with 3-bromopropanenitrile (2a) to furnish 3a.
Fig. 6: Regioselective zincation of indazole precursors
Nickel-catalyzed photoredox coupling in place of Pd-catalyzed amination. ChemAIRS identified a nickel-catalyzed photoredox coupling as a promising alternative that may offer advantages in cost, greener considerations, and scalability - depending on reaction conditions and implementation. Although the initial proposal invoked a Buchwald–Hartwig reaction with an in situ Pd–BINAP catalyst, follow-up analysis with the Condition Search tool indicated that a nickel-catalyzed photoredox pathway could likewise serve as a viable route to 5a [23] (Figure 7).
Fig. 7: Nickel-catalyzed photoredox coupling
Streamlined acid-promoted cyclization. ChemAIRS outlined an acid-promoted cyclization to form the piperidine-2,6-dione ring, followed by Boc deprotection (8b). While illustrated as two steps, these transformations could plausibly be telescoped into a one-pot process, simplifying the workflow and helping to maintain the step count (Figure 5).
In addition, although the iodoindazole starting material (1) (Figure 4) is commercially available, ChemAIRS noted it can be readily prepared in one step from 6-bromo-3-iodo-1-methyl-1H-indazole - an alternative nearly seven times cheaper per gram.
This case study shows that ChemAIRS can be a valuable helper for synthetic chemists - able to explore different ideas, suggest more efficient and affordable synthetic routes, and reduce bottlenecks in drug development. Most importantly, it highlights the power of synergy between human expertise and AI: while scientists bring creativity and deep knowledge, AI expands the horizon by offering new perspectives and complementary solutions. Together, they can accelerate innovation and make complex chemistry more accessible.
References
Hatzi, K.; Melnick, A. M. Breaking Bad in the Germinal Center: How Deregulation of BCL6 Contributes to Lymphomagenesis. Trends in Molecular Medicine 20(6), 343–352 (2014). doi:10.1016/j.molmed.2014.03.001
Liu, Y. et al. The oncoprotein BCL6 enables solid tumor cells to evade genotoxic stress. eLife 11, e69255 (2022). doi:10.7554/eLife.69255
Liongue, C. et al. B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. International Journal of Molecular Sciences 25(20), 10968 (2024). doi:10.3390/ijms252010968
Basso, K.; Dalla-Favera, R. BCL6: Master Regulator of the Germinal Center Reaction and Key Oncogene in B-Cell Lymphomagenesis. Advances in Immunology 105, 193–210 (2010). doi:10.1016/S0065-2776(10)05007-8
Ranuncolo, S. M. et al. BCL6-mediated attenuation of DNA damage sensing triggers growth arrest and senescence through a p53-dependent pathway in a cell context-dependent manner. Journal of Biological Chemistry, 283(33), 22565–22572 (2008). doi:10.1074/jbc.M803490200
Ci, W.; Polo, J. M.; Melnick, A. M. B-cell lymphoma 6 and the molecular pathogenesis of diffuse large B-cell lymphoma. Current Opinion in Hematology 15(4), 381–390 (2008). doi:10.1097/MOH.0b013e328302c7df
Liongue, C.; Almohaisen, F. L. J.; Ward, A. C. B Cell Lymphoma 6 (BCL6): A Conserved Regulator of Immunity and Beyond. International Journal of Molecular Sciences 25 (20), 10968 (2024). doi:10.3390/ijms252010968
Wlodarska, I. et al. Frequent occurrence of BCL6 rearrangements in nodular lymphocyte-predominant Hodgkin lymphoma but not in classical Hodgkin lymphoma. Blood 101(2), 706–710 (2003). doi:10.1182/blood-2002-05-1592
Weniger, M. A.; Küppers, R. Molecular biology of Hodgkin lymphoma. Leukemia, 35(4), 968–981 (2021). doi:10.1038/s41375-021-01204-6
Kamada, Y. et al. Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach. Journal of Medicinal Chemistry, 60(10), 4358–4368 (2017). doi:10.1021/acs.jmedchem.7b00313
Cerchietti, L. C. et al. A Small-Molecule Inhibitor of BCL6 Kills DLBCL Cells In Vitro and In Vivo. Cancer Cell, 17(4), 400–411 (2010). doi:10.1016/j.ccr.2009.12.050
Kerres, N. et al. Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6. Cell Reports 20(12), 2860–2875 (2017). doi:10.1016/j.celrep.2017.08.081
Rana, S., et al. Small molecule induced polymerization of BCL6 facilitates SIAH1 mediated degradation. Signal Transduction and Targeted Therapy, 6(1), 142 (2021). doi:10.1038/s41392-021-00556-w
McCoull, W. et al. Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6. ACS Chemical Biology, 13(11), 3131–3141 (2018). doi:10.1021/acschembio.8b00698
McCoull, W. et al. Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High-Affinity Macrocyclic Inhibitors. Journal of Medicinal Chemistry, 60(10), 4386–4402 (2017). doi:10.1021/acs.jmedchem.7b00359
Groocock, L. et al. BMS-986458: A Potential First-in-Class, Highly Selective, Potent and Well-Tolerated BCL6 Ligand-Directed Degrader (LDD) Demonstrates Multi-Modal Anti-Tumor Efficacy for the Treatment of B-Cell Non-Hodgkin’s Lymphoma. Blood, 144 (Supplement 1), 957 (2024). doi:10.1182/blood-2024-210951
Heterocyclic Compounds as Modulators of BCL6 as Ligand-Directed Degraders. WO2023212147A1, published November 2, 2023; priority date April 27, 2023. Assignee: Celgene Corporation / Bristol-Myers Squibb.
Békés, M., Langley, D. R., & Crews, C. M. PROTAC Targeted Protein Degraders: The Past Is Prologue. Nature Reviews Drug Discovery, 21(3), 181–200 (2022). doi:10.1038/s41573-021-00371-6
Gao, H.; Sun, X.; Rao, Y PROTAC Technology: Opportunities and Challenges. ACS Medicinal Chemistry Letters, 11(3), 237–240 (2020). doi:10.1021/acsmedchemlett.9b00597
Osman, J. et al. Methods to accelerate PROTAC drug discovery. Biochemical Journal, 482(13), 921–937 (2025). doi:10.1042/BCJ20243018
Yang, C.; Tripathi, R.; Wang, B. Click Chemistry in the Development of PROTACs. RSC Chemical Biology, 5, 189–197 (2024). doi:10.1039/D3CB00199G
Unsinn, A.; Knochel, P. Regioselective zincation of indazoles using TMP₂Zn and Negishi cross-coupling with aryl and heteroaryl iodides. Chemical Communications, 48 (21), 2680–2682 (2012). doi:10.1039/C2CC17804D
Song, G. et al. Ni-Catalyzed Photochemical C–N Coupling of Amides with (Hetero)aryl Chlorides. Chemistry – A European Journal 29(37), e202300458 (2023). doi:10.1002/chem.202300458