UCHL1 Inhibitors, Modifications, and Uses Thereof (UCLA Case No. 2026-123)

UCLA researchers in the Department of Molecular & Medical Pharmacology and have developed novel, highly potent small-molecule inhibitors of UCHL1 that selectively suppress tumor growth and metastasis in aggressive cancers with favorable in vivo safety profiles.

BACKGROUND: Ubiquitin carboxy-terminal hydrolase L1 (UCHL1) is a dual-function enzyme that regulates protein stability by recycling ubiquitin through deubiquitination while also exhibiting ubiquitin ligase activity of proteasomal degradation. Dysregulation of UCHL1 has been implicated in multiple diseases, including neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, as well as a wide range of cancers. Notably, UCHL1 is highly expressed in aggressive neuroendocrine malignancies such as small cell lung cancer (SCLC), neuroendocrine prostate cancer (NEPC), and poorly differentiated neuroblastoma, where it contributes to tumor growth, metastasis, and maintenance of neuroendocrine identity. Thus, UCHL1 is a promising target for therapeutics for a vast array of diseases.

INNOVATION: UCLA researchers led by Dr. Tanya Stoyanova and Dr. Michael Jung have developed a new class of small-molecule UCHL1 inhibitors developed through rational modification of a known tool compound. These compounds exhibit enhanced potency, selectivity, and in vivo efficacy relative to prior inhibitors. In addition to effectively inhibiting UCHL1 deubiquitinase activity, researchers showed that lead compounds from this class demonstrate nanomolar inhibitory activity, strong suppression of tumor growth and metastatic potential in xenograft models, and high tolerability via both oral and IV administration. Thus, these compounds hold immense translational potential as first-in-class UCHL1-targeted therapeutics.

POTENTIAL APPLICATIONS:

• Targeted therapy for neuroendocrine cancers and neuroblastoma
• Treatment of other UCHL1-driven malignancies (e.g. breast, lung, colorectal, lymphoma)
• Research tools to probe ubiquitin signaling and proteostasis
• Development of minimally invasive cancer biomarkers
• Expansion into non-oncologic UCHL1-associated diseases (e.g. Alzheimer’s)

ADVANTAGES:

• Significantly higher potency than existing inhibitors
• Target selectivity (preferentially targets UCHL1-positive cells)
• Significant tumor growth suppression with both oral and IV delivery
• Favorable safety profile

DEVELOPMENT-TO-DATE: The inventors have developed and structurally validated multiple novel UCHL1 inhibitors and identified lead compounds with superior potency and selectivity. They have shown in vitro efficacy and UCHL1 enzymatic inhibition, as well as in vivo anti-tumor efficacy in xenograft models. They have also identified maximum tolerated doses and toxicity profiles for oral and IV dosing.

Related Papers (from the inventors only):

1. Liu S, Chai T, Garcia-Marques F, Yin Q, Hsu EC, Shen M, Shaw Toland AM, Bermudez A, Hartono AB, Massey CF, Lee CS, Zheng L, Baron M, Denning CJ, Aslan M, Nguyen HM, Nolley R, Zoubeidi A, Das M, Kunder CA, Howitt BE, Soh HT, Weissman IL, Liss MA, Chin AI, Brooks JD, Corey E, Pitteri SJ, Huang J, Stoyanova T. UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas. Cell Rep Med. 2024 Feb 20;5(2):101381. doi: 10.1016/j.xcrm.2023.101381. Epub 2024 Jan 19. PMID: 38244540; PMCID: PMC10897521.

Keywords: UCHL1, ubiquitin-proteosome system, protein degradation, proteostasis, small-molecule inhibitors, targeted cancer therapy, precision oncology, cancer, neuroendocrine cancer, xenograft models, ubiquitin carboxy-terminal hydrolase L1, deubiquitinase inhibitor