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. 2023 Jan 12;14(2):199–210. doi: 10.1021/acsmedchemlett.2c00502

Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor

Ahmed Mamai †,*, Anh M Chau †, Brian J Wilson †, Iain D Watson †, Babu B Joseph †, Pandiaraju R Subramanian †, Monzur M Morshed †, Justin A Morin †, Michael A Prakesch †, Tianbao Lu §, Pete Connolly §, Douglas A Kuntz ‡, Neil C Pomroy ‡, Gennady Poda †,⊥, Kong Nguyen †, Richard Marcellus †, Graig Strathdee †, Brigitte Theriault †, Ratheesh Subramaniam †, Mohammed Mohammed †, Ayome Abibi †, Manuel Chan †, Jeffrey Winston †, Taira Kiyota †, Elijus Undzys †, Ahmed Aman †,⊥, Nigel Austin §, Marc Du Jardin §, Kathryn Packman §, Ulrike Phillippar ∥, Riccardo Attar §, James Edwards §, Jeff O’Meara †, David E Uehling †, Rima Al-awar †,#,7, Gilbert G Privé ‡,8,9,*, Methvin B Isaac †,*
PMCID: PMC9923840  PMID: 36793435

Abstract

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B cell lymphoma 6 (BCL6), a highly regulated transcriptional repressor, is deregulated in several forms of non-Hodgkin lymphoma (NHL), most notably in diffuse large B-cell lymphoma (DLBCL). The activities of BCL6 are dependent on protein–protein interactions with transcriptional co-repressors. To find new therapeutic interventions addressing the needs of patients with DLBCL, we initiated a program to identify BCL6 inhibitors that interfere with co-repressor binding. A virtual screen hit with binding activity in the high micromolar range was optimized by structure-guided methods, resulting in a novel and highly potent inhibitor series. Further optimization resulted in the lead candidate 58 (OICR12694/JNJ-65234637), a BCL6 inhibitor with low nanomolar DLBCL cell growth inhibition and an excellent oral pharmacokinetic profile. Based on its overall favorable preclinical profile, OICR12694 is a highly potent, orally bioavailable candidate for testing BCL6 inhibition in DLBCL and other neoplasms, particularly in combination with other therapies.

Keywords: non-Hodgkin lymphoma (NHL), BCL6, protein−protein interaction, co-repressor, metabolic stability, oral bioavailability

Diffuse large B-cell lymphoma (DLBCL) is a highly malignant form of non-Hodgkin lymphoma (NHL) that constitutes about 40% of all lymphoma diagnoses.1 The current chemotherapy regimen of rituximab, cyclophosphamide, hydroxyldaunorubicin, vincristine, and prednisone (R-CHOP) has significantly improved cure rates.2 However, with the exception of rituximab (a chimeric anti-CD20 monoclonal antibody), no other targeted agents have been adopted in frontline therapy for DLBCL. This is largely due to the heterogeneity of DLBCL and the inability to identify the oncogenic drivers responsible for a patient’s disease.3 With the increasing availability of targeted therapies, personalized oncology has the promise of more effective treatments for malignancies while reducing toxic side effects. The promise of B cell lymphoma 6 (BCL6) as a therapeutic target is supported by its deregulated expression in some germinal center (GC)-derived lymphomas, by the observation that many lymphoma cell lines are dependent on BCL6 expression, and by the relatively restricted expression patterns of BCL6 suggesting limited toxicity to normal cells.4,5 Recent studies have also unveiled oncogenic functions of BCL6 in acute lymphoblastic leukemia, chronic myeloid leukemia, and other cancers.6,7 However, despite compelling data implicating BCL6 as a driver in some forms of DLBCL and other cancers,8,9 transcription factors such as BCL6 have traditionally been deemed “undruggable”.

BCL6 is a member of the BTB-ZF (broad-complex, tramtrack, and bric-a-brac zinc finger) family of transcription factors. In these proteins, the N-terminal BTB domain binds to epigenetic modifiers through protein–protein interactions, while the C-terminal zinc fingers mediate site-specific DNA binding.10,11 The BCL6 BTB domain interacts directly with the NCoR1 (nuclear receptor co-repressor 1) and SMRT (silencing mediator for retinoid or thyroid-hormone receptors) or NCoR2 (nuclear receptor co-repressor 2) co-repressors to recruit HDAC3 (histone deacetylase 3) complexes, and with the BCOR (BCL6 co-repressor) to recruit PRC2 (polycomb repressive complex 2)-like complexes. All three of these co-repressors use 17-amino-acid motifs to bind to a solvent-exposed “lateral groove” formed by the two chains of the BCL6 BTB homodimer. BCL6 has other functions, and mice with a genetic deletion of the gene have severe inflammation due to effects that appear to be independent of the N-terminal BTB domain.12 Agents that bind to the BCL6 BTB lateral groove compete for co-repressor binding and can reverse the repression activities of BCL6.13 In principle, the selective targeting of protein–protein interactions (PPIs) in the BCL6 BTB domain is a more precise form of inhibition of BCL6 relative to complete inactivation or removal of the protein.

Recently, a number of small molecules have been described that bind to a pocket in the BCL6 BTB lateral groove and disrupt BCL6-co-repressor interactions.14 These include 79-6 (1a),13 FX1 (1b),15 XXI (2),16,17 BI-3802 (3),18,19 CCT369260 (4),20 and GSK137 (5)21 among others (Figure 1). While these compounds all bind to similar sites in the lateral groove pocket, they represent diverse chemical scaffolds that inhibit BCL6 with different modes of action. For example, while 79-6, FX1, XXI, and GSK137 bind to the lateral groove in a reversible manner, BI-3802 binds to the same pocket and induces the proteasomal degradation of BCL618 by a novel mechanism involving the ligand-induced polymerization of BCL6 and subsequent ubiquitination by the SIAH1 (seven in absentia homolog 1) E3 ligase.19 A proteolysis-targeting chimera (PROTAC) version of XXI was constructed by the addition of a thalidomide group to recruit the E3 ligase cereblon.17 Despite encouraging cell-based activity, many of these ligands were reported to suffer from poor bioavailability, thus limiting their use in animal studies. A recent study disclosed CCT369260,20 an independently discovered BCL6 inhibitor with a similar core structure as BI-3802, but with better pharmacokinetic properties. The publication disclosing GSK137 as orally bioavailable revealed from in vivo pharmacokinetics and target engagement analyses that three-times daily dosing was required, suggesting a high clearance profile. Given the fact that novel BCL6-based therapy would likely require a chronic dosing regimen, the discovery of an inhibitor with good oral bioavailability and favorable clearance would be the most suitable option for disease management.

Figure 1.

Figure 1

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Representative examples of reported BCL6 inhibitors.

We carried out a virtual screen targeting the lateral groove site identified in the co-crystal structure with 79-612 and tested the top-scoring compounds in a surface plasmon resonance (SPR) assay to measure direct binding to the BTB domain, and in a competitive fluorescence polarization (FP) assay to measure the displacement of a labelled SMRT peptide from the domain (Supplemental Figure S1). This led to the identification of pyrrolopyridone 6 as a novel hit (IC50 = 440 μM, KD = 282 μM). Initial optimization efforts included the replacement of the southern acetanilide moiety with various substituted aromatic and heteroaromatic amines (Table 1). Incorporation of the ortho-chloro- and fluoro-substituted anilides in 7, 8, and 9 led to a slight improvement in potency in the FP and SPR assays, whereas the unsubstituted phenyl analog 10 demonstrated a significant loss in activity, suggesting that the electronic property of the amide aromatic ring is critical for activity. Encouragingly, the incorporation of a 3-chloropyridin-4-amine substituent improved the potency by 3-fold relative to 6 (compound 11, IC50 = 132 μM, KD = 119 μM, Table 1), while the 4-amino-3-chlorobenzonitrile or 4-amino-3-fluorobenzonitrile substituents afforded compounds with significantly weaker BCL6 inhibitory properties (compare 11 with 12 and 13, Table 1). Of the additional ortho-substituted pyridyl-4-amines investigated, only the Cl substituent retained acceptable BCL6 inhibition levels (compound 11). One-carbon homologation of the acetanilide moiety of 6 or the introduction of an α-methyl group (compounds 14 and 15, respectively) resulted in complete loss of binding (KD: ND and IC50 > 500 μM).

Table 1. Early SAR Exploration of the Southern Amide.

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Having identified the optimal linker as the methylene group for the amide, we undertook additional structure–activity relationship (SAR) studies to explore via scaffold hopping various heteroarene rings as potential replacements for the pyrrolopyridone core of 6. Initial attempts involved the synthesis of the fused tricyclic triazolo analog 16 that resulted in a 3- to 4-fold loss of potency. Notably, the pyrrolopyrimidone 17 showed a 6- to 7- fold improvement in potency in the BCL6 biochemical assay (IC50 = 20 μM, KD = 21 μM, Table 2). However, the introduction of an additional nitrogen atom to the 6,5-heterocycle in the pyrazolopyrimidone 18 resulted in a 4-fold loss in potency. Replacing the pyrrolopyrimidone core 17 with 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine 19 (isomer of 17) or 4-amino-7H-pyrrolo[2,3-d]pyrimidine 20 led to complete loss of binding, whereas the 2-amino-3,4a,7,7a-tetrahydro-4H-pyrrolo[2,3-d]pyrimidin-4-one analog 21 exhibited inhibitory activity similar to that of 17, suggesting the carbonyl group of the pyrrolopyrimidone core is critical for binding.

Table 2. Exploration of SAR: Scaffold Hopping.

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Co-crystal structures of the BCL6 BTB domain in complex with 11 and 17 at 1.71 Å and 1.17 Å resolution, respectively, confirmed the virtual screen pose with a near-perfect overlap of the predicted and observed ligand atoms based on the superposition of the protein chains (Figure 2, Supplemental Table S1). The structure revealed key interactions involving both chains of the homodimer, which include an H-bond between the acetamide NH and the backbone carbonyl of Met51 (chain A), an H-bond between the pyrimidone carbonyl and the backbone NH of Glu115(A), and the stacking of the ortho-Cl pyridyl between the phenolic ring of Tyr58(A) and the guanidino of Arg24(B), which is in a planar bidentate association with the side-chain amide of Asn21(B). The structures also revealed the key open region, suggesting an additional vector at the C3 position for further optimization of the series (Figure 2B). Such evidence prompted us to design chemistry coupling strategies to explore how to best occupy this pocket.

Figure 2.

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Crystal structure of the human BCL6-BTB dimer in complex with compound 11. (A) The 1.71 Å structure of 11 is shown on the solvent-accessible surface of the BCL6 BTB domain dimer, with the chains colored in pink and light blue. (B) Closeup view of the binding pocket. The arrow indicates a vector from the C3 position of the pyrrolopyrimidone to a pocket indicated by the asterisk. Hydrogen bonds are indicated with dotted lines, and key protein residues are labeled. (C) Overlay of the experimental structure of 11 (orange carbons) with the docked position of virtual hit 6 (yellow carbons) based on the overlay of the BCL6 protein chains.

We next explored substituted aromatic moieties at the C3 position (Table 3). The mono-substituted aromatic analogues 22 (3-cyanophenyl, KD = 11 μM) and 23 (4-hydroxyphenyl, KD = 14 μM) had potencies similar to that of 17. Remarkably, the combination of the 3-cyano and 4-hydroxy substituents in the disubstituted molecule 24 resulted in a 200-fold improvement in potency (KD = 0.054 μM) over the mono-substituted aromatic analogues, representing a major breakthrough in the lead optimization efforts. At these potencies, we had reached the floor of the FP assay and therefore turned to the SPR to further guide the SAR study. The co-crystal structure of 24 showed H-bonds between the cyano nitrogen and the main-chain NH of Val117(A), and between the ligand hydroxyl and the δ1 nitrogen of His14(B) (Figure 3).

Table 3. SAR Exploration at the 3-Position of Pyrrolopyrimidinones: C3 Substitutions.

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Figure 3.

Figure 3

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Co-crystal structure of human BCL6-BTB dimer with compound 24 at 1.22 Å resolution.

Additional SAR studies with C3 disubstituted and trisubstituted phenolic groups (25–28) resulted in loss of potency, whereas the trisubstituted analog 29 with a methyl group proximal to the 3-cyano-4-hydroxy substituents was well tolerated, with a 2- to 3-fold increase in potency relative to 24.

We next added two cellular assays to our screening cascade: a BCL6 reporter assay in SUDHL4 cells, and a cell growth assay using Karpas-422 (Supplemental Figure S2). We observed excellent correlations between BCL6 binding, cellular activity, and growth inhibition (Supplementary Figures S3 and S4). SUDHL4 and Karpas-422 are DLBCL cell lines with high levels of BCL6 expression. We measured encouraging antiproliferative activity for 24 and 29 (Table 4); however, these compounds suffered from poor metabolic stability in liver microsomes due to extensive phase II glucuronidation of the phenolic moiety (data not shown). In order to improve the glucuronidation profile and hence the metabolic properties of the series, we replaced the aromatic nitrile group with a carboxamide with the hypothesis that intramolecular hydrogen bonding between the phenolic OH and the adjacent carboxamide would reduce the availability of the phenolic hydroxy group to the UDP-glucuronosyl transferase. Supporting our hypothesis, the resulting 2-hydroxybenzamide (salicylamide) 30 displayed a significant improvement in metabolic stability along with a 6-fold increase in passive permeability (Caco-2 A-B = 0.6 for 30 vs Caco-2 A-B = 0.1 for 24, Table 4) relative to 24. Interestingly, compound 30 also exhibited improved cell potencies despite the 2-fold decrease in biochemical potency, suggesting that the replacement of the nitrile with carboxamide had a favorable impact on the cellular permeability.

Table 4. SAR Exploration of Pyrrolopyrimidinones: Combination of C3 and Pyridine Substitutions.

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a

Percent of the parent compound remaining after 1 h incubation with MLM or HLM (mouse and human liver microsomes).

Encouraged by the improved metabolic stability and cellular properties exhibited by 30, we revisited modifications of the southern chloro-pyridyl moiety. As shown in Table 4, the introduction of morpholine substituents resulted in 3- to 6-fold increase in anti-BCL6 activity (compare 31 and 32 with 30, Table 4). These inhibitors also exhibited significantly improved in vitro permeability and cellular activity.

Further exploration of the C3-substituted 2-hydroxybenzamides to include the 3-chloro-substituted analogs 33 and 34a (S-enantiomer) afforded molecules with excellent BCL6 inhibitory potency. The co-crystal structure of BCL6 BTB with 34a confirmed the intramolecular phenol-acetamide H-bond in the northern ring and revealed an extended H-bonded network with the protein. The structure also showed that the morpholine exited the southern pocket that accommodates the chloropyridyl group and has high solvent exposure. The corresponding enantiomer 34b (R-enantiomer) gave similar potency results. We next replaced the morpholines with N-alkyl piperazines with the expectation that lowering the compound’s lipophilicity (clogD7.4 = 1.83 vs clogD7.4 = 1.16) would improve the solubility and human liver microsome (HLM) stability. The resulting molecule 35 (KD = 0.011 μM, Table 4) exhibited improved human metabolic stability but also retained BCL6 inhibition potency relative to 34a. The 3-fluoro-substituted analog 36 maintained both potency and metabolic stability but led to a decrease in permeability. In contrast, the 4-fluoro-substituted analog 37 resulted in a loss of potency and metabolic stability but with significantly improved permeability properties. However, the 3,4-difluoro-substituted analogs 38 and 39 show a slight decrease in potency but offer significantly improved metabolic stability. Additional piperazine modifications such as the more polar oxetanylpiperazine analog 40 or the dimethyl-ring-substituted derivative 41 suffered from significant losses in cellular potency. Further replacements of the 3,4-difluoro-2-hydroxybenzamide with other disubstituted groups as in 42 and 43 provided compounds that were at least 3- to 4-fold less potent relative to 38.

We next set out to explore the impact of fluorine substitution in the southern (S)-dimethylpiperazine chloro-pyridine ring. The first such analog, 44, displayed 9 nM BCL6 potency but demonstrated higher turnover in human microsomal incubations. The corresponding 3,4-difluoro-2-hydroxybenzamide derivative 45 maintained potency with improved metabolic stability and good passive permeability. Additional exploration of the salicylamide led to compounds 46, 47, and 50 with reduced potency. The 3-fluoro-2-hydroxybenzamide 48 and the methylenedioxy-2-hydroxybenzamide 49, which were 3- to 11-fold more potent than 45, suffered from poor metabolic stability.

With the optimized piperazinyl-pyridine (R5 = H or F) and substituted salicylamide group (3,4-difluoro-2-hydroxybenzamide and methylenedioxy-2-hydroxybenzamide) in place, the role of the substituent at the C6 position (R6) of the pyrrolopyrimidone core was investigated (Table 5). The introduction of the methyl group at R6 (compound 51 and 52) maintained potency and favorable metabolic stability with a significant increase in permeability relative to 38 and 45. Although the C6 methyl analog of the methylenedioxy-2-hydroxybenzamide derivative 53 (KD = 0.001 μM) displayed excellent potency and improved permeability (Caco-2 A-B = 8.0), it too suffered from poor metabolic stability. The corresponding ethylenedioxy-2-hydroxybenzamide 54 exhibited not only decreased BCL6 potency but also poor metabolism and low permeability. Further SAR investigation suggested that the R6 methyl group could be replaced by electron-withdrawing substituents such as CF3 (55) and electron-donating groups such as a methoxy (56), but the BCL6-BTB affinity was significantly reduced despite the remarkable gains in passive permeability.

Table 5. Further SAR Exploration of Pyrrolopyrimidinones: Combination of C3, C6, and Pyridine Substitutions.

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a

Percent of the parent compound remaining after 1 h incubation with MLM or HLM.

We next attempted to further elaborate compounds 52 and 53 by exploring the effects of cyclizing the R6 methyl substituent onto pyrimidone nitrogen, as shown in Figure 4 and Table 6. We initially employed a five-membered ring (n = 1, Table 6) and identified compound 57 as a sub-nM BCL6 biochemical inhibitor with low nM cellular activity. Overall, 57 had an approximately 2-fold improvement over the uncyclized compound 53 but was also highly unstable toward HLM and thus required additional optimization. We then made a cyclized version of compound 52 with the expectation that the 3,4-difluoro-2-hydroxybenzamide should favorably impact the HLM stability. Gratifyingly, the resulting molecule 58 (OICR12694) not only exhibited improved HLM clearance properties, but also displayed potent cellular BCL6 inhibition (KD = 0.005 μM) and antiproliferative activity (SUDHL4 Luc, EC50 = 0.089 μM; Karpas-422 growth inhibition IC50 = 0.092 μM). Further expansion of the ring resulted in the six- (59, n = 2) and seven- (60, n = 3) membered compounds, but both molecules suffered from significantly reduced potency and poorer metabolic stability in liver microsomes.

Figure 4.

Figure 4

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Design of a novel tricyclic series of inhibitors: discovery of OICR12694.

Table 6. Tricyclic Series SAR.

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Among all the analogues depicted in Tables 1 to Table 6, compound 58 (OICR12694) displayed the best combination of BCL6 inhibitory activity, in vitro metabolic stability, and permeability characteristics. The 1.30 Å co-crystal structure of 58 (OICR12694) is shown in Figure 5. A representative synthesis of our BCL6 inhibitors is described in the Supporting Information.

Figure 5.

Figure 5

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Co-crystal structure of human BCL6-BTB dimer bound to 58 (OICR12694). Hydrogen bonds are indicated with dotted lines, and key protein residues are labeled.

Encouraged by the overall in vitro profile of 58 (OICR12694), we carried out pharmacokinetics studies of this compound. Gratifyingly, 58 exhibited low clearance and good oral exposure in mice and dogs (Table 7). Minimal inhibitory activity was confirmed across a panel of diverse kinases (Eurofins 109 kinome panel profile @ 1 μM, Supporting Information). Compound 58 (OICR12694) also showed greater than 100-fold binding selectivity toward other BTB proteins, including BAZF, MIZ1, PLZF, FAZF, Kaiso, and LRF (Supplemental Table S2).

Table 7. Pharmacokinetics Parameters of OICR12694 in Mouse and Dog.

Parameter Mouse Dog
Dosage (mg/kg) iv/po 1.0/5.0 1.0/5.0
CL (mL/min/kg) 22 9.1
Vss(L/kg) 1.1 2.0
T1/2 (h) 1.6 6.1
AUC (ng·h/ml) po 1338 4290
Cmax (nM) po 1310 2270
oral BA, F (%) 36 47
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Finally, 58 (OICR12694) did not impair the function of various cytochrome P450 (CYPs) isoforms when tested in vitro against these enzymes (IC50 values of >10 μM for CYP 1A2, 2C8, 2C9, 2C19, 2D6, and 3A4). The molecule also exhibited minimal inhibition of the human ether-à-go-go-related gene (hERG) ion channel (data not shown) and was negative in Ames and micronucleus in vitro assessments of genotoxicity.

In summary, starting from a 282 μM virtual screen hit, we have used a structure-based design SAR study to identify a novel series of structurally distinct, potent, selective, and orally bioavailable BCL6-BTB inhibitors. These efforts have culminated in the discovery of a 5 nM inhibitor, 58 (OICR12694). To our knowledge, 58 (OICR12694) is among the most potent orally bioavailable BCL6-BTB inhibitors disclosed to date. OICR12694 was tested in multiple in vitro assays and showed a potent growth suppression of BCL6-dependent cell lines such as Karpas-422. This compound was shown to be a selective binder to the BCL6-BTB relative to other BTB family members. Moreover, a battery of in vitro toxicity assays showed that OICR12694 has a clean safety profile. Finally, this compound showed very good oral bioavailability in both mice and dogs. Overall, our discovery of potent and orally bioavailable BCL6 inhibitors should facilitate the dissection of the role and the relevance of BCL6 modulation in certain cancers such as DLBCL or other BCL6-driven diseases.

Acknowledgments

The authors acknowledge funding and support from the Johnson and Johnson Research and Development team, the OICR Drug Discovery, and the Ontario Ministry of Research and Innovation.

Glossary

Abbreviations

BCL6

B cell lymphoma 6

DLBCL

diffuse large B-cell lymphoma

NHL

non-Hodgkin lymphoma

R-CHOP

rituximab, cyclophosphamide, hydroxyldaunorubicin, vincristine, and prednisone

GC

germinal center

BTB-ZF

broad-complex, tramtrack, and bric-a-brac zinc finger

NCoR1

nuclear receptor co-repressor 1

NCoR2

nuclear receptor co-repressor 2

BCOR

BCL6 co-repressor

SMRT

silencing mediator for retinoid or thyroid-hormone receptors

HDAC3

histone deacetylase 3

PRC2

polycomb repressive complex 2

SIAH1

seven in absentia homolog 1

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsmedchemlett.2c00502.

  • Details for the synthetic procedures, compound characterization, assays, kinase profiling, ADME, and crystallographic results (PDF)

Accession Codes

Coordinates for the crystal structures included here have been deposited in the Protein Data Bank with IDs 7LZQ, 7LWE, 7LWF, 7LZS, and 7LWG.

The authors declare no competing financial interest.

This paper was originally published ASAP on January 12, 2023, with a typo in the surname of co-author Michael A. Prakesch. The corrected version was reposted on January 13, 2023.

Supplementary Material

ml2c00502_si_001.pdf (1.4MB, pdf)

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