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Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders.

<div class='caption-title'>Final Step Diversificationof Benzimidazolone N3 Position</div>
<div class='caption-title'>Synthesis of Key Intermediate 16</div>
<div class='caption-title'>Synthesis of Compounds from Table 3, Investigating DifferentSubstitution Patterns on Pyrimidine or Pyridine Rings</div>
Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S
OpenAccess logo J Med Chem 63 4047-4068 (2020)
Related entries: 6tof, 6tog, 6toh, 6toj, 6tok, 6tol, 6tom, 6ton, 6too

Cited: 20 times
EuropePMC logo PMID: 32275432

Abstract

Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.

Articles - 6toi mentioned but not cited (1)

  1. Achieving In Vivo Target Depletion through the Discovery and Optimization of Benzimidazolone BCL6 Degraders. Bellenie BR, Cheung KJ, Varela A, Pierrat OA, Collie GW, Box GM, Bright MD, Gowan S, Hayes A, Rodrigues MJ, Shetty KN, Carter M, Davis OA, Henley AT, Innocenti P, Johnson LD, Liu M, de Klerk S, Le Bihan YV, Lloyd MG, McAndrew PC, Shehu E, Talbot R, Woodward HL, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Hoelder S. J Med Chem 63 4047-4068 (2020)


Reviews citing this publication (6)

  1. Advances in targeting 'undruggable' transcription factors with small molecules. Henley MJ, Koehler AN. Nat Rev Drug Discov 20 669-688 (2021)
  2. Molecular Glues: The Adhesive Connecting Targeted Protein Degradation to the Clinic. Sasso JM, Tenchov R, Wang D, Johnson LS, Wang X, Zhou QA. Biochemistry 62 601-623 (2023)
  3. Unifying Catalysis Framework to Dissect Proteasomal Degradation Paradigms. Rodriguez-Rivera FP, Levi SM. ACS Cent Sci 7 1117-1125 (2021)
  4. Targeting Protein Degradation Pathways in Tumors: Focusing on their Role in Hematological Malignancies. Wolska-Washer A, Smolewski P. Cancers (Basel) 14 3778 (2022)
  5. Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment. Wu H, Yao H, He C, Jia Y, Zhu Z, Xu S, Li D, Xu J. Acta Pharm Sin B 12 3548-3566 (2022)
  6. Targeted Protein Degradation: Clinical Advances in the Field of Oncology. Salama AKAA, Trkulja MV, Casanova E, Uras IZ. Int J Mol Sci 23 15440 (2022)

Articles citing this publication (13)

  1. Small-molecule-induced polymerization triggers degradation of BCL6. Słabicki M, Yoon H, Koeppel J, Nitsch L, Roy Burman SS, Di Genua C, Donovan KA, Sperling AS, Hunkeler M, Tsai JM, Sharma R, Guirguis A, Zou C, Chudasama P, Gasser JA, Miller PG, Scholl C, Fröhling S, Nowak RP, Fischer ES, Ebert BL. Nature 588 164-168 (2020)
  2. Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond. Ai Y, Hwang L, MacKerell AD, Melnick A, Xue F. J Med Chem 64 4333-4358 (2021)
  3. Optimizing Shape Complementarity Enables the Discovery of Potent Tricyclic BCL6 Inhibitors. Davis OA, Cheung KJ, Brennan A, Lloyd MG, Rodrigues MJ, Pierrat OA, Collie GW, Le Bihan YV, Huckvale R, Harnden AC, Varela A, Bright MD, Eve P, Hayes A, Henley AT, Carter MD, McAndrew PC, Talbot R, Burke R, van Montfort RLM, Raynaud FI, Rossanese OW, Meniconi M, Bellenie BR, Hoelder S. J Med Chem 65 8169-8190 (2022)
  4. Rewiring cancer drivers to activate apoptosis. Gourisankar S, Krokhotin A, Ji W, Liu X, Chang CY, Kim SH, Li Z, Wenderski W, Simanauskaite JM, Yang H, Vogel H, Zhang T, Green MR, Gray NS, Crabtree GR. Nature 620 417-425 (2023)
  5. Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket. Lloyd MG, Huckvale R, Cheung KJ, Rodrigues MJ, Collie GW, Pierrat OA, Gatti Iou M, Carter M, Davis OA, McAndrew PC, Gunnell E, Le Bihan YV, Talbot R, Henley AT, Johnson LD, Hayes A, Bright MD, Raynaud FI, Meniconi M, Burke R, van Montfort RLM, Rossanese OW, Bellenie BR, Hoelder S. J Med Chem 64 17079-17097 (2021)
  6. Improved Binding Affinity and Pharmacokinetics Enable Sustained Degradation of BCL6 In Vivo. Huckvale R, Harnden AC, Cheung KJ, Pierrat OA, Talbot R, Box GM, Henley AT, de Haven Brandon AK, Hallsworth AE, Bright MD, Akpinar HA, Miller DSJ, Tarantino D, Gowan S, Hayes A, Gunnell EA, Brennan A, Davis OA, Johnson LD, de Klerk S, McAndrew C, Le Bihan YV, Meniconi M, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Bellenie BR, Hoelder S. J Med Chem 65 8191-8207 (2022)
  7. Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays. Pierrat OA, Liu M, Collie GW, Shetty K, Rodrigues MJ, Le Bihan YV, Gunnell EA, McAndrew PC, Stubbs M, Rowlands MG, Yahya N, Shehu E, Talbot R, Pickard L, Bellenie BR, Cheung KJ, Drouin L, Innocenti P, Woodward H, Davis OA, Lloyd MG, Varela A, Huckvale R, Broccatelli F, Carter M, Galiwango D, Hayes A, Raynaud FI, Bryant C, Whittaker S, Rossanese OW, Hoelder S, Burke R, van Montfort RLM. Sci Rep 12 18633 (2022)
  8. Discovery of OICR12694: A Novel, Potent, Selective, and Orally Bioavailable BCL6 BTB Inhibitor. Mamai A, Chau AM, Wilson BJ, Watson ID, Joseph BB, Subramanian PR, Morshed MM, Morin JA, Prakesch MA, Lu T, Connolly P, Kuntz DA, Pomroy NC, Poda G, Nguyen K, Marcellus R, Strathdee G, Theriault B, Subramaniam R, Mohammed M, Abibi A, Chan M, Winston J, Kiyota T, Undzys E, Aman A, Austin N, Du Jardin M, Packman K, Phillippar U, Attar R, Edwards J, O'Meara J, Uehling DE, Al-Awar R, Privé GG, Isaac MB. ACS Med Chem Lett 14 199-210 (2023)
  9. Congress 30th Annual GP2A Medicinal Chemistry Conference. O'Boyle NM, Helesbeux JJ, Meegan MJ, Sasse A, O'Shaughnessy E, Qaisar A, Clancy A, McCarthy F, Marchand P. Pharmaceuticals (Basel) 16 432 (2023)
  10. Determination of Ligand-Binding Affinity (Kd) Using Transverse Relaxation Rate (R2) in the Ligand-Observed 1H NMR Experiment and Applications to Fragment-Based Drug Discovery. Liu M, Mirza A, McAndrew PC, Thapaliya A, Pierrat OA, Stubbs M, Hahner T, Chessum NEA, Innocenti P, Caldwell J, Cheeseman MD, Bellenie BR, van Montfort RLM, Newton GK, Burke R, Collins I, Hoelder S. J Med Chem 66 10617-10627 (2023)
  11. Discovery of an In Vivo Chemical Probe for BCL6 Inhibition by Optimization of Tricyclic Quinolinones. Harnden AC, Davis OA, Box GM, Hayes A, Johnson LD, Henley AT, de Haven Brandon AK, Valenti M, Cheung KJ, Brennan A, Huckvale R, Pierrat OA, Talbot R, Bright MD, Akpinar HA, Miller DSJ, Tarantino D, Gowan S, de Klerk S, McAndrew PC, Le Bihan YV, Meniconi M, Burke R, Kirkin V, van Montfort RLM, Raynaud FI, Rossanese OW, Bellenie BR, Hoelder S. J Med Chem 66 5892-5906 (2023)
  12. Polymorphic structures of 3-phenyl-1H-1,3-benzo-diazol-2(3H)-one. Hong D, Lee K. Acta Crystallogr E Crystallogr Commun 79 534-537 (2023)
  13. Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer. Wu M, Xie J, Xing Y, Zhang L, Chen H, Tang B, Zhou M, Lv S, Huang D, Jian S, Zhou C, Liu M, Guo W, Chen Y, Yi Z. Int J Biol Sci 20 486-501 (2024)


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