Stress Modulator
Platform

Stress Modulator
Platform

Stress Modulator
Platform

Targeting the Adaptive Stress Response

Through our expertise in stress biology, we have pioneered two differentiated, clinical-stage adaptive stress response modulator programs. Our molecules modulate key aspects of the adaptive stress response that enable tumor survival and limit the ability of T cells to eliminate cancer cells. Our PERK and GCN2 programs have reproducibly resulted in tumor regressions and anti-cancer immunity in numerous tumor models as monotherapy as well as in combination with standard of care therapies.

How We Disrupt the Stress Response

The UPR and ISR are activated by various cellular stressors including, but not limited to oxygen starvation (hypoxia), amino acid deprivation, glucose deprivation, mutations, and the accumulation of misfolded proteins within the endoplasmic reticulum. Many of these stressors are intrinsic to the tumor, while others are extrinsically mediated by a patient’s therapeutic regimen.

Activation of the UPR and ISR within tumor cells can enable the tumor to survive and avoid detection by the immune system.  Modulation of key adaptive stress pathway kinases, PERK and GCN2, may modulate this adaptive stress response and disrupt a tumor’s survival mechanisms.

HC-5404

A UPR Inhibitor

Mechanism of Action

HC-5404 is a differentiated, orally bioavailable small molecule inhibitor of PKR-like endoplasmic reticulum kinase (PERK). This kinase is activated when the Unfolded Protein Response (UPR) detects Endoplasmic Reticulum (ER) stress, the process by which unfolded and misfolded proteins are recognized by the UPR, leading to activation and downstream signaling that is propagated by PERK. Signaling via this pathway enables cancer cells to trigger a number of mechanisms that allow them to  survive in the face of numerous stressors.

Clinical Development

In preclinical studies,  we have observed robust anti-tumor activity with HC-5404 in different tumor types, including primary tumors as well as those that metastasized to the lung and liver. HC-5404 is under investigation in a Phase 1a trial as a monotherapy for the treatment of renal cell carcinoma (RCC), gastric cancer, and other advanced tumors.

Fast Track Designation

HC-7366

An ISR Inhibitor

Mechanism of Action

HC-7366 is a differentiated, orally bioavailable small molecule modulator of General Control Nonderepressible 2 (GNC2). GCN2 plays a critical role activating the Integrated Stress Response (ISR) pathway in response to amino acid deprivation and / or hypoxia. Notably, GCN2 signaling impacts immune cell function by reducing their ability to effectively detect and eliminate cancer cells. Thus, modulating GCN2 signaling could improve anti-tumor immunity.

Clinical Development

In preclinical studies, we have observed robust anti-tumor and immunomodulatory activity with HC-7366 in a variety of solid tumors and hematological malignancies. HC-7366 is under investigation in a Phase 1a/b trial as monotherapy for treatment of HNSCC, CRC, Bladder, and other advanced tumors.

A Number of Standard of Care Agents Activate the Adaptive Stress Response


Molecule
Tumor Type
Cisplatin
Lung
Cisplatin
Gastric
Epirubicin
Adenocarcinoma
Oxaliplatin
Colorectal
Doxorubicin
Hepatocellular
Doxorubicin
Breast Cancer
Salinomycin
Non-small cell lung
Methotrexate
Ovarian
5-Fluorouracil
Hepatocellular
Breast Cancer
Imiquimod
Melanoma
Paclitaxel
Adenocarcinoma
Paclitaxel
FBXW7 Deficient
Paclitaxel
Breast Cancer
N/A
Oropharyngeal
N/A
Breast Cancer
Cetuximab
HNSCC
Sorafenib
Hepatocellular
Sunitinib
Renal cell
Vemurafenib
Thyroid
Vemurafenib
Melanoma & CRC
Trametinib
FBXW7 deficient
Drug Classification
Molecule
Tumor Type
UPR/ISR Sensor
Modes of Resistance
Reference
Alkylating Agents
Cisplatin
Lung
PERK
Protective autophagy
Cisplatin
Gastric
GCN2
Anti-oxidant defense/increased nutrient transport
Epirubicin
Adenocarcinoma
GCN2
Apoptosis inhibition
Oxaliplatin
Colorectal
PERK
Drug efflux
Antibiotic Agents
Doxorubicin
Hepatocellular
PERK
Apoptosis inhibition / Drug efflux
Doxorubicin
Breast Cancer
PERK
Apoptosis inhibition
Salinomycin
Non-small cell lung
PERK
Protective autophagy
Antimetabolites
Methotrexate
Ovarian
PERK
Protective autophagy
5-Fluorouracil
Hepatocellular
PERK
Apoptosis inhibition
Breast Cancer
PERK
Proliferation
Immunosuppression
Imiquimod
Melanoma
PERK
Apoptosis inhibition
Plant Alkaloids
Paclitaxel
Adenocarcinoma
GCN2
Decreased proliferation
Paclitaxel
FBXW7 Deficient
GCN2
Decreased proliferation
Paclitaxel
Breast Cancer
PERK
Apoptosis inhibition
Radiotherapy
N/A
Oropharyngeal
PERK
Apoptosis inhibition
N/A
Breast Cancer
PERK
Apoptosis inhibition
Targeted Agents
Cetuximab
HNSCC
PERK
Protective autophagy
Sorafenib
Hepatocellular
PERK
Protective autophagy
Sunitinib
Renal cell
PERK
NF-B pro-survival pathway
Vemurafenib
Thyroid
PERK
Protective autophagy
Vemurafenib
Melanoma & CRC
GCN2
Increased nutrient transport
Trametinib
FBXW7 deficient
GCN2
Apoptosis inhibition