CACHE Challenge #4: Targeting the TKB Domain of the E3 ligase CBLB, an Immuno-Oncology Target
Тип публікації :
Препринт
Дата випуску :
10 липня 2026 р.
Автор(и) :
Madhushika Silva
Oleksandra Herasymenko
Abd Al‐Aziz A. Abu‐Saleh
Suzanne Ackloo
R. Al-Awar
C.H. Arrowsmith
Ryota Ashizawa
David J. Bearss
Beck Hartmut
Kevin P. Bishop
Vincent Blay
Hugo J. Bohórquez
Albina Bolotokova
Duanhua Cao
Irene Chau
Lin Chen
Sandro Cosconati
Wim Dehaen
Kristina Edfeldt
Elisa Gibson
Gediminas Gumbis
Christoph Gorgulla
Anders Gunnarsson
Rachel J. Harding
Laurent Hoffer
Anders Hogner
Douglas R. Houston
Oleksii Hrabovskyi
John J. Irwin
Diane Joseph- McCarthy
Andrea Karlova
Sergei Kotelnikov
Dima Kozakov
Uta Lessel
Peter Loppnau
Wei Lu
Kyle Medley
Miles McGibbon
Yurii Moroz
Charuvaka Muvva
Benito Natale
Boyang Ni
Eva Nittinger
Tudor I. Oprea
Brooks Paige
Keunwan Park
Gennady Poda
Konstantin Popov
Mykola Protopopov
Vera Pütter
Edina Rosta
Michele Roggia
Yogesh Sabnis
Christopher Secker
Olha Semenenko
Conrad V. Simoben
Olga O. Tarkhanova
Dakota Treleaven
Alexander Tropsha
David Uehling
Hariprasad Vankayalapati
Jude Wells
James Wellnitz
Yvonne Westermaier
Lars Wortmann
Jie Yu
J C Zhang
R Zhang
Mingyue Zheng
Shuangjia Zheng
Yuchen Zhou
Sara Ziadat
Levon Halabelian
Matthieu Schapira
eKNUTSHIR URL :
Журнал :
ChemRxiv
Цитування :
[APA 7] Madhushika, S., Oleksandra, H., Abd, A. A., Suzanne, A., R., A., C.H., A., Ryota, A., David, J. B., Beck, H., Kevin, P. B., Vincent, B., Hugo, J. B., Albina, B., Duanhua, C., Irene, C., Lin, C., Sandro, C., Wim, D., Kristina, E., Elisa, G., Gediminas, G., Christoph, G., Anders, G., Rachel, J. H., Laurent, H., Anders, H., Douglas, R. H., Oleksii, H., John, J. I., Diane, J. M., Andrea, K., Sergei, K., Dima, K., Uta, L., Peter, L., Wei, L., Kyle, M., Miles, M., Yurii, M., Charuvaka, M., Benito, N., Boyang, N., Eva, N., Tudor, I. O., Brooks, P., Keunwan, P., Gennady, P., Konstantin, P., Mykola, P., Vera, P., Edina, R., Michele, R., Yogesh, S., Christopher, S., Olha, S., Conrad, V. S., Olga, O. T., Dakota, T., Alexander, T., David, U., Hariprasad, V., Jude, W., James, W., Yvonne, W., Lars, W., Jie, Y., J, C. Z., R, Z., Mingyue, Z., Shuangjia, Z., Yuchen, Z., Sara, Z., Levon, H., & Matthieu, S. (2026). CACHE Challenge #4: Targeting the TKB Domain of the E3 ligase CBLB, an Immuno-Oncology Target. ChemRxiv,. https://doi.org/10.26434/chemrxiv.15005792/v2
[ДСТУ] CACHE Challenge #4: Targeting the TKB Domain of the E3 ligase CBLB, an Immuno-Oncology Target / S. Madhushika та ін. ChemRxiv. 2026. DOI: 10.26434/chemrxiv.15005792/v2 (дата звернення: 11.09.2026).
The Critical Assessments of Computational Hit-finding Experiments (CACHE) are prospective benchmarking exercises where small molecule ligands predicted for a nominated protein of interest are procured and tested experimentally. In CACHE #4, 23 participating teams each selected up to 100 compounds designed to bind the E3 ligase CBLB, an immuno-oncology target. The organizers released the first public structure of CBLB in complex with a known ligand at the outset of the challenge to enable the discovery of chemically novel molecules. Out of the 1,688 compounds collectively predicted, ten compounds from nine participants showed some sign of activity (primary hits), but only two were convincingly confirmed (validated hits) across multiple biophysical binding assays and in subsequent analogs, and only one of them was chemically novel. The apparent difficulty of finding novel CBLB ligands, previously reflected by the chemical similarity of inhibitors from the patent literature, suggests that potent CBLB hit molecules were either rare in the screened commercial libraries, or that computational methods may have struggled to retrieve presumably present but weak ligands, or that the conformational dynamics of the binding site was not sufficiently accounted for. The successful method was strikingly atypical. Selection from a chemical binding similarity classifier followed by a Random Forest binding affinity predictor trained on inhibitors from the patent literature were refined using a diffusion-model binding pose predictor. The road to an ML-driven breakthrough in computational hit-finding can take unexpected turns. Which of these turns reveal novel horizons and which are mere distractions will best be investigated and answered collectively. The discovery in CACHE #4 of a novel series of CBLB ligands is not a trivial achievement and may inform medicinal chemistry efforts towards clinical candidates that complement immune checkpoint inhibition to elicit antitumor immune response in cancer patients.
Якщо не вказано інше, ця робота розповсюджується на умовах ліцензії Attribution 4.0 International