For Investigators & Partners
SHY-ONC6-101 (Luca-1)
SHY-ONC6 is a first-in-class oral inhibitor of ATPases in the 19S Regulatory Particle of the proteasome currently being evaluated in the Phase 1 Luca-1 study in advanced solid tumors.
This page provides an overview of the program, preclinical evidence, and opportunities for clinical and strategic collaboration.
A Glimpse into Our Program
Phase 1a/1b
PHASE
Small Molecule
MODALITY
19S Proteasome ATPases
TARGET
Oral, Once Daily
ADMINISTRATION
Luca-1
TRIAL
Up to 8 US Sites
SITES
Advanced Solid Tumors
POPULATION
Recruiting
STATUS
Scientific Differentiation
SHY-ONC6:
A First-in-Class Oral Inhibitor of ATPases in the 19S Regulatory Particle of the Proteasome
SHY-ONC6 is a novel, orally bioavailable small molecule that inhibits the ATPase activity of the 19S Regulatory Particle of the 26S proteasome. It is the first clinical candidate to engage this target. Approved proteasome inhibitors, bortezomib, carfilzomib, and ixazomib, are dipeptide analogues that block the proteolytic sites of the 20S Core Particle and are approved only in multiple myeloma and mantle cell lymphoma. SHY-ONC6’s distinct mechanism, chemical structure, favorable pharmacokinetic profile, and route of administration may broaden the therapeutic reach of proteasome modulation into solid tumors.
Mechanism of action studies confirm ATPases within the 19S Regulatory Particle as SHY-ONC6's target. In particular, tumor cell line studies demonstrate:
Increased Ubiquitinated Proteins
Increased total protein ubiquitination levels in cells.
Apoptosis Induction
Activation of caspases and induction of apoptosis.
No Inhibition of 20S Proteolytic β-Site Activity
No inhibition of the proteolytic β sites activity of purified 26S proteasome. The three FDA-approved proteasome inhibitors target the proteolitic beta-site; SHY-ONC6 does not.
Selective Inhibition of ATPases in the 19S Regulatory Particle
Concentration-dependent inhibition of 19S ATPase activity.
SHY-ONC6
Target
19S Regulatory Particle
26S Proteasome
FDA Approved Drugs’ Target
Bortezomib, Carfilzomib, Ixazomib
20S Core Particle
Mechanism of Action
The full 26S proteasome degrades ubiquitinated proteins through the coordinated action of two subunits: the 19S Regulatory Particle and the 20S Core Particle. The 19S Regulatory Particle recognizes ubiquitinated protein substrates, unfolds them and translocates them into the 20S Core Particle in an ATP-dependent manner. The proteolysis occurs in the 20S Core Particle. SHY-ONC6 inhibits ATPases within the 19S Regulatory Particle that unfold and translocate the proteins.
Preclinical Evidence
~80%
Broad in vitro activity
In a Broad Institute PRISM study, SHY-ONC6 demonstrated robust in vitro activity, with IC50 values in the range of 1 - 100 nM in approximately 80% of the 869 human solid and blood-borne human tumor-derived cell lines tested. In approximately 35 in vitro studies conducted by SHY, SHY-ONC6 demonstrated similarly compelling IC50 values.
In vivo xenograft activity
Once-daily oral SHY-ONC6 was tested in 15 solid tumor models, in 8 of which tumor regression was detected and in 7 tumor growth inhibition was detected. The drug was also tested in 3 hematologic tumor models, in 2 of which tumor regression was detected and in 1 tumor growth inhibition was detected. Several of these tumor models correspond to tumor types eligible for Luca-1.
Pharmacokinetics
SHY-ONC6 has a more favorable oral PK profile in mice than the FDA approved proteasome inhibitors. Notably, in mice, SHY-ONC6 penetrated the blood brain barrier, in contrast to the FDA approved drugs, which do not. This may be relevant to tumor types with frequent CNS involvement and to the protocol’s allowance for participants with stable CNS or meningeal metastases.
To request a more detailed preclinical package or to discuss the program, please contact: businessdevelopment@shytherapeutics.com.
IND-enabling toxicology
SHY-ONC6 was well tolerated in GLP 28-day daily repeat dose studies in rats and dogs.
Design
Adaptive Bayesian Optimal Interval (BOIN) design with accelerated single-patient titration permitted for up to the first two dose levels. Subsequent dose escalation increments are between >33% and <100%, governed by integrated safety, tolerability, and PK.
Single Participant
Single Participant
Adaptive BOIN
Recommended Phase 2 Dose Range
21
days
Schedule
SHY-ONC6 is administered orally, once daily, fasted, in continuous 21-day cycles. Intra-patient dose escalation is permitted under prespecified conditions.
Eligible tumor types
Eligible tumor types include triple-negative breast, HR+ breast, colon, gastric, hepatocellular, NSCLC (adenocarcinoma and squamous), mesothelioma, pancreatic, hormone-resistant prostate, and soft-tissue sarcoma. Other tumor types may be considered with Medical Monitor approval.
Breast
Pancreatic
NSCLC
Sarcoma
Prostate
Colon
Gastric
Mesothelioma
Objectives
Primary
Safety and tolerability; MTD and Recommended Phase 2 Dose (RP2D) range.
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Secondary
PK profile; preliminary anti-tumor activity (RECIST v1.1; PCWG3 for prostate).
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Exploratory
ctDNA dynamics; intratumoral PD and predictive biomarkers.
Get in Touch
For Investigators
We welcome inquiries from qualified Phase 1 investigators interested in participating in Luca-1 or future SHY-ONC6 studies.
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Inquiries should include: site name, principal investigator, prior Phase 1 oncology experience, and indications of particular interest.
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The current list of activated sites and contact information for patient referrals is maintained on ClinicalTrials.gov under study identifier SHY-ONC6-101.
For Strategic Partners
SHY Therapeutics welcomes discussions with pharmaceutical and biotechnology companies interested in licensing, co-developing, or entering into a strategic partnership around SHY-ONC6 and the broader 19S proteasome regulatory particle program.
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For qualified interested parties and under appropriate confidentiality, we will be pleased to discuss the preclinical SHY-ONC6 data package, IND-enabling toxicology, manufacturing and CMC status, IP position, and clinical development plan.
SHY-ONC6 is an investigational compound. Statements regarding its mechanism, preclinical activity, and clinical development reflect current data and plans, which may change as the program advances. This page is intended for clinical investigators, scientific collaborators, and prospective partners; it is not intended as solicitation for investment in any security.