CACHE Challenge #4: Targeting the TKB Domain of the E3 ligase CBLB, an Immuno-Oncology Target

作者：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 · 发表于：ChemRxiv · 年份：2026 · DOI：10.26434/chemrxiv.15005792/v2 · 研究领域：Protein Degradation and Inhibitors、Computational Drug Discovery Methods、Cancer Immunotherapy and Biomarkers

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 ...