Developing small molecule therapeutics that non-covalently modulate the activity of ATPases & GTPases
GTPases and ATPases are essential proteins involved in the regulation of almost every major cellular process, including metabolism, signal transduction, proliferation, and adhesion proliferation. Dysregulation of GTPases and ATPases underlies a broad spectrum of human diseases, including cancer, neurodegeneration, and infectious diseases.
SHY’s drug development strategy leverages the essential roles of ATPases and GTPases by designing small molecules that specifically compete for their interactions with ATP or GTP, respectively, and then modulate their function. SHY’s portfolio includes its lead oncology candidate, SHY-ONC6, an oral proteasome inhibitor now in a Phase 1 clinical trial in solid tumors;
a non-covalent Ras superfamily of small GTPases multi-target therapeutic cancer small molecule program; and programs targeting bacterial and fungal pathogens. SHY retains full rights to its programs and a growing dossier of related issued and pending composition of matter, mechanism of action, and use patents worldwide.
SHY's pipeline
SHY’s drug development strategy leverages the essential roles of ATPases and GTPases by designing small molecules that specifically compete for their interactions with ATP or GTP, respectively, and then modulate their function. SHY’s portfolio includes its lead oncology candidate, SHY-ONC6, an oral proteasome inhibitor now in a Phase 1 clinical trial in solid tumors; a non-covalent Ras Superfamily of Small GTPases multi-target cancer therapeutic; and programs targeting bacterial and fungal pathogens. SHY retains full rights to its programs and a growing dossier of related issued and pending composition of matter, mechanism of action, and use patents worldwide.
SHY's pipeline
Program
Target
Discovery
Lead Optimization
IND-Enabling
Phase 1
Oncology
SHY-ONC6
Inhibitor of ATPases in the 19S Regulatory Particle of the Proteasome
(Luca-1, underway)
Oncology
Ras Superfamily of small GTPases Multi-Target
SHY-ONC6
SHY-ONC6 inhibits ATPases in the proteasome 19S Regulatory Particle and is now an anticancer therapeutic clinical candidate.
The Food and Drug Administration has authorized, and SHY is now undertaking, a Phase 1 clinical trial of SHY-ONC6 in solid tumors. The trial is called Luca-1.
Development Status
In June 2026, SHY initiated Luca-1 to treat nine types of solid tumors that have shown positive pre-clinical results when treated with SHY-ONC6. SHY plans to refine target indications in later stages of Luca-1 and subsequent trials.
SHY-ONC6 pre-clinical efficacy and safety data suggest it can enable the use of proteasome inhibition as a method for treating solid as well as hematologic tumors.
Three FDA approved drugs (Bortezomib, Carfilzomib, and Ixazomib) have validated the clinical and commercial importance of the proteasome ubiquitin system as a therapeutic oncology target. They are approved for the treatment of two hematologic oncological indications, multiple myeloma and mantle cell lymphoma. However, they are limited in their use by their toxicity profiles and physicochemical limitations, and have not proven efficacious in clinical trials for the treatment of solid tumors. They are dipeptides that target the proteolytic beta sites in the proteasome 20S Core Particle.
SHY-ONC6’s mechanism of action and structure are entirely different from the approved proteasome inhibitor drugs. It is a novel, oral small molecule that selectively inhibits ATPases within the 19S Regulatory Particle of the proteasome. SHY-ONC6 has demonstrated significant efficacy in [18] pre-clinical xenograft models of hematologic and solid tumors at well tolerated doses.
Mechanism of Action
SHY-ONC6 is a selective, non-covalent, small molecule inhibitor of a subset of the AAA+ ATPases in the proteasome 19S regulatory particle. The 19S Regulatory Particle is responsible for recognizing and binding ubiquitinated proteins, removing their ubiquitin chains (deubiquitination), unfolding them, and translocating them into the proteasome 20S Core Particle for proteolytic degradation in an ATP-dependent manner. SHY-ONC6’s inhibition of the subset of AAA+ ATPases interferes with this process and induces apoptosis.
Preclinical highlights:
-
Potent anti-tumor activity in multiple solid tumor models (e.g., breast, colon, gastric, liver, lung, mesothelioma, pancreatic, prostate, and soft-tissue sarcoma)
-
Favorable tolerability profile
-
Oral bioavailability
-
Crosses blood-brain barrier
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 Efficacy
In mouse xenograft models, SHY-ONC6 has demonstrated robust oral efficacy, achieving well over 100% tumor growth inhibition (regression) in a range of human-derived tumor models. Once-daily oral SHY-ONC6 was tested in 15 solid tumor models, of which 8 regressed and 7 were inhibited, and in 3 hematologic tumor models, of which 2 regressed and 1 was inhibited. These included human derived models of colon, gastric, mesothelioma, lung (small cell, and non-small cell), and pancreatic cancers; and, multiple myeloma and Acute Promyelocytic Leukemia (APL), all known for their poor prognoses. Several of these solid tumor types correspond to tumor types eligible for Luca-1. In all of these studies, SHY-ONC6 was well tolerated at efficacious doses.
Safety and Tolerability
Extensive independent preclinical studies in rats and dogs have demonstrated that SHY-ONC6 is well-tolerated at effective doses, with dose-dependent, reversible effects observed at exposures above the anticipated Luca-1 range.
-
Anti-Fungal
Undisclosed
Ras Superfamily of Small GTPases Multi-Target Cancer Therapeutics
SHY is in the lead optimization stage of developing orally bioavailable small molecules for the treatment of cancer that non-covalently inhibit members of the Ras Superfamily of small GTPases. Candidates in this program demonstrate inhibition of multiple Ras Superfamily GTPases (including, for example, wild type KRas, KRas mutants, Rac and Rho); significant in vitro inhibition of cellular proliferation (including in human cell lines resistant to approved therapeutics that target KRas), and significant in vivo tumor growth inhibition at well tolerated doses. Subject to the success of ongoing studies, SHY has a goal of selecting a clinical candidate from this program by Q1 2027.
SHY was founded on two hypotheses. First, that the GTP-binding sites of KRas and other members of the Ras super family of small GTPases are non-covalently druggable targets. And, second, that developing orally bioavailable small molecules that target multiple members of the Ras Superfamily could be an effective therapeutic strategy in a similar way that the targeting of multiple receptor tyrosine kinases has proven to be a therapeutic strategy with significant clinical and commercial impact.
SHY has demonstrated that the affinity of Ras Superfamily member GTP-binding sites to GTP is in the range of ~250 nM.
Consistent with this finding, SHY has developed a library of novel small molecules that non-covalently compete with GTP binding to the GTP binding sites of multiple Ras Superfamily members (including, for example, wild type KRas, KRas mutants, Rac and Rho) and modulate downstream signaling by them.
A number of Ras Superfamily members have been identified and validated as targets for the development of cancer therapeutics. Most prominent among them is KRas. KRas mutations are associated with approximately 30% of all human tumors, which has made them long-time therapeutic oncology targets. Two covalently bound compounds targeting KRas G12C mutations, Lumakras (sotorasib) and Krazati (adagrasib), had impressive initial clinical effects, were approved by the FDA, but proved in post-approval clinical use to have limited durations of effect. More recently, a new generation of inhibitors targeting both wild type and several KRas mutants have demonstrated significant response rates and longer duration of tumor progression benefit.
SHY believes that the multi-target Ras Superfamily small molecules it is developing may complement existing KRas-targeted therapies while also addressing the significant unmet need in patients with tumors that current KRas inhibitors cannot treat.
For a fuller account of SHY’s founding hypothesis, the 1980s/1990s affinity measurement background, and the scientific rationale for the multi-target Ras Superfamily approach, please see our publication in Molecular Cancer Therapeutics and our Company History page.
Anti-Bacterial
Undisclosed
Anti-Fungal Program and NIH Grant Funding
SHY is developing novel chemical scaffolds that demonstrate in vitro and in vivo activity comparable to standards of care against a range of fungal strains of public health concern. Lead development is continuing in this program which is supported by a grant from the National Institute of Allergy and Infectious Diseases of the NIH.
The research is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R43AI186577. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Neuromuscular
Undisclosed
Anti-Bacterial Program
SHY is developing novel chemical scaffolds that target gram negative and gram-positive bacterial pathogens. Program compounds demonstrate specific potent in vitro activity, comparable to standards of care, against a range of serious drug-resistant microbial strains.
Neuromuscular Program
SHY has developed molecules that reverse diseased tissue phenotypes in in vivo models of a significant neuromuscular disease. Based on currently available resources, SHY does not anticipate advancing this program further before 2027.
Ras Superfamily of Small GTPases Multi-Target Cancer Therapeutics
SHY is in the lead optimization stage of developing orally bioavailable small molecules for the treatment of cancer that non-covalently inhibit members of the Ras Superfamily of small GTPases. Candidates in this program demonstrate inhibition of multiple Ras Superfamily GTPases (including, for example, wild type KRas, KRas mutants, Rac and Rho); significant in vitro inhibition of cellular proliferation (including in human cell lines resistant to approved therapeutics that target KRas), and significant in vivo tumor growth inhibition at well tolerated doses. Subject to the success of ongoing studies, SHY has a goal of selecting a clinical candidate from this program by Q1 2027.
SHY was founded on two hypotheses. First, that the GTP-binding sites of KRas and other members of the Ras super family of small GTPases are non-covalently druggable targets. And, second, that developing orally bioavailable small molecules that target multiple members of the Ras Superfamily could be an effective therapeutic strategy in a similar way that the targeting of multiple receptor tyrosine kinases has proven to be a therapeutic strategy with significant clinical and commercial impact.
SHY has demonstrated that the affinity of Ras Superfamily member GTP-binding sites to GTP is in the range of ~250 nM.
Consistent with this finding, SHY has developed a library of novel small molecules that non-covalently compete with GTP binding to the GTP binding sites of multiple Ras Superfamily members (including, for example, wild type KRas, KRas mutants, Rac and Rho) and modulate downstream signaling by them.
A number of Ras Superfamily members have been identified and validated as targets for the development of cancer therapeutics. Most prominent among them is KRas. KRas mutations are associated with approximately 30% of all human tumors, which has made them long-time therapeutic oncology targets. Two covalently bound compounds targeting KRas G12C mutations, Lumakras (sotorasib) and Krazati (adagrasib), had impressive initial clinical effects, were approved by the FDA, but proved in post-approval clinical use to have limited durations of effect. More recently, a new generation of inhibitors targeting both wild type and several KRas mutants have demonstrated significant response rates and longer duration of tumor progression benefit.
SHY believes that the multi-target Ras Superfamily small molecules it is developing may complement existing KRas-targeted therapies while also addressing the significant unmet need in patients with tumors that current KRas inhibitors cannot treat.
For a fuller account of SHY’s founding hypothesis, the 1980s/1990s affinity measurement background, and the scientific rationale for the multi-target Ras Superfamily approach, please see our publication in Molecular Cancer Therapeutics and our Company History page.
Ras Superfamily of small GTPases Multi-Target
SHY-ONC6
SHY-ONC6 inhibits ATPases in the proteasome 19S Regulatory Particle and is now an anticancer therapeutic clinical candidate.
The Food and Drug Administration has authorized, and SHY is now undertaking, a Phase 1 clinical trial of SHY-ONC6 in solid tumors. The trial is called Luca-1.
Development Status
In June 2026, SHY initiated Luca-1 to treat nine types of solid tumors that have shown positive pre-clinical results when treated with SHY-ONC6. SHY plans to refine target indications in later stages of Luca-1 and subsequent trials.
SHY-ONC6 pre-clinical efficacy and safety data suggest it can enable the use of proteasome inhibition as a method for treating solid as well as hematologic tumors.
Three FDA approved drugs (Bortezomib, Carfilzomib, and Ixazomib) have validated the clinical and commercial importance of the proteasome ubiquitin system as a therapeutic oncology target. They are approved for the treatment of two hematologic oncological indications, multiple myeloma and mantle cell lymphoma. However, they are limited in their use by their toxicity profiles and physicochemical limitations, and have not proven efficacious in clinical trials for the treatment of solid tumors. They are dipeptides that target the proteolytic beta sites in the proteasome 20S Core Particle.
SHY-ONC6’s mechanism of action and structure are entirely different from the approved proteasome inhibitor drugs. It is a novel, oral small molecule that selectively inhibits ATPases within the 19S Regulatory Particle of the proteasome. SHY-ONC6 has demonstrated significant efficacy in [18] pre-clinical xenograft models of hematologic and solid tumors at well tolerated doses.
Mechanism of Action
SHY-ONC6 is a selective, non-covalent, small molecule inhibitor of a subset of the AAA+ ATPases in the proteasome 19S regulatory particle. The 19S Regulatory Particle is responsible for recognizing and binding ubiquitinated proteins, removing their ubiquitin chains (deubiquitination), unfolding them, and translocating them into the proteasome 20S Core Particle for proteolytic degradation in an ATP-dependent manner. SHY-ONC6’s inhibition of the subset of AAA+ ATPases interferes with this process and induces apoptosis.
Preclinical highlights:
-
Potent anti-tumor activity in multiple solid tumor models (e.g., breast, colon, gastric, liver, lung, mesothelioma, pancreatic, prostate, and soft-tissue sarcoma)
-
Favorable tolerability profile
-
Oral bioavailability
-
Crosses blood-brain barrier
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 Efficacy
In mouse xenograft models, SHY-ONC6 has demonstrated robust oral efficacy, achieving well over 100% tumor growth inhibition (regression) in a range of human-derived tumor models. Once-daily oral SHY-ONC6 was tested in 15 solid tumor models, of which 8 regressed and 7 were inhibited, and in 3 hematologic tumor models, of which 2 regressed and 1 was inhibited. These included human derived models of colon, gastric, mesothelioma, lung (small cell, and non-small cell), and pancreatic cancers; and, multiple myeloma and Acute Promyelocytic Leukemia (APL), all known for their poor prognoses. Several of these solid tumor types correspond to tumor types eligible for Luca-1. In all of these studies, SHY-ONC6 was well tolerated at efficacious doses.
Safety and Tolerability
Extensive independent preclinical studies in rats and dogs have demonstrated that SHY-ONC6 is well-tolerated at effective doses, with dose-dependent, reversible effects observed at exposures above the anticipated Luca-1 range.
-
Inhibitor of ATPases in the 19S Regulatory Particle of the Proteasome
Luca-1, underway
Target
Discovery
Lead Optimization
IND-Enabling
Phase 1
Oncology
Anti-Fungal Program and NIH Grant Funding
SHY is developing novel chemical scaffolds that demonstrate in vitro and in vivo activity comparable to standards of care against a range of fungal strains of public health concern. Lead development is continuing in this program which is supported by a grant from the National Institute of Allergy and Infectious Diseases of the NIH.
The research is supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under Award Number R43AI186577. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Undisclosed
Target
Discovery
Lead Optimization
IND-Enabling
Phase 1
Anti-Fungal
Anti-Bacterial Program
SHY is developing novel chemical scaffolds that target gram negative and gram-positive bacterial pathogens. Program compounds demonstrate specific potent in vitro activity, comparable to standards of care, against a range of serious drug-resistant microbial strains.
Undisclosed
Target
Discovery
Lead Optimization
IND-Enabling
Phase 1
Anti-Bacterial
Neuromuscular Program
SHY has developed molecules that reverse diseased tissue phenotypes in in vivo models of a significant neuromuscular disease. Based on currently available resources, SHY does not anticipate advancing this program further before 2027.
Undisclosed
Target
Discovery
Lead Optimization
IND-Enabling
Phase 1
Neuromuscular
We are excited by the number of opportunities we believe SHY has to develop first in class therapeutics to benefit patients with significant unmet medical needs. Borrowing an expression used by competitive rowers, we believe we have a lot of open water ahead.
Yaron Hadari & Michael Schmertzler
Founder and Chief Executive Officer & Founder and Executive Chair
A portfolio of proprietary small molecule non-covalent ATPase and GTPase modulators.
SHY Therapeutics retains full ownership of all pharmacophores and molecules developed in its programs.
