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 candidates have been observed to modulate key aspects of the adaptive stress response that enable tumor survival and limit the ability of the immune system to eliminate cancer cells. Preclinically, we have observed our PERK and GCN2 programs to have reproducible results in tumor regressions and anti-cancer immunity in numerous animal models as a monotherapy as well as in combination with standard of care therapies.

Adapted from McGrath et al. (2018) PMID: 30248920

Disrupting the Stress Response

The UPR and ISR pathways are activated by various cellular stressors that can be intrinsic or extrinsic to the tumor, including, but not limited to, oxygen starvation (hypoxia), amino acid deprivation, glucose deprivation, mutations, the accumulation of misfolded proteins within the endoplasmic reticulum and exposure to cancer treatments.

Activation of the UPR and ISR pathways within cancer cells can enable tumors to survive stressors, avoid detection by the immune system, and develop treatment resistance and the capacity for metastatic spread. We believe that targeting key adaptive stress pathway kinases, PERK and GCN2, may modulate this adaptive stress response and disrupt tumor adaptive and survival mechanisms.

HC-5404

A UPR Inhibitor

Mechanism of Action

HC-5404 is a differentiated, orally bioavailable investigational small molecule inhibitor of PERK. This kinase is activated when the UPR detects ER stress, the process by which unfolded and misfolded proteins are recognized by the UPR, leading to activation and downstream signaling that is mediated by PERK. Signaling via this pathway enables cancer cells to trigger a number of mechanisms that enable 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 models, 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 solid tumors.

Fast Track Designation

HC-7366

An ISR Modulator

Mechanism of Action

HC-7366 is a differentiated, orally bioavailable investigational small molecule modulator of GCN2. GCN2 plays a critical role in activating the Integrated Stress Response (ISR) pathway in response to stressors, such as 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, we believe that 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 models of solid tumors and hematological malignancies. HC-7366 is under investigation in a Phase 1a/b trial as monotherapy for treatment of HNSCC, CRC, transitional cell carcinoma of the 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	Shi et al. (2016)
	Cisplatin	Gastric	GCN2	Anti-oxidant defense/increased nutrient transport	Wang et al. (2016)
	Epirubicin	Adenocarcinoma	GCN2	Apoptosis inhibition	Alasiri et al. (2020)
	Oxaliplatin	Colorectal	PERK	Drug efflux	Salaroglio et al. (2017)
Antibiotic Agents	Doxorubicin	Hepatocellular	PERK	Apoptosis inhibition / Drug efflux	Li et al. (2015)
	Doxorubicin	Breast Cancer	PERK	Apoptosis inhibition	McGrath et al. (2016)
	Salinomycin	Non-small cell lung	PERK	Protective autophagy	Li et al. (2013)
Antimetabolites	Methotrexate	Ovarian	PERK	Protective autophagy	Shen et al. (2015)
	5-Fluorouracil	Hepatocellular	PERK	Apoptosis inhibition	Liu et al. (2016)
	5-Fluorouracil	Breast Cancer	PERK	Proliferation	Yao et al. (2020)
Immunosuppression	Imiquimod	Melanoma	PERK	Apoptosis inhibition	El-Khattouti et al. (2016)
Plant Alkaloids	Paclitaxel	Adenocarcinoma	GCN2	Decreased proliferation	Alasiri et al. (2020)
	Paclitaxel	FBXW7 Deficient	GCN2	Decreased proliferation	Sanchez-Burgos et al. (2022)
	Paclitaxel	Breast Cancer	PERK	Apoptosis inhibition	McGrath et al. (2016)
Radiotherapy	N/A	Oropharyngeal	PERK	Apoptosis inhibition	Reyes et al. (2021)
Radiotherapy	N/A	Breast Cancer	PERK	Apoptosis inhibition	McGrath et al. (2016)
Targeted Agents	Cetuximab	HNSCC	PERK	Protective autophagy	Lei et al. (2016)
	Sorafenib	Hepatocellular	PERK	Protective autophagy	Zhou et al. (2019)
	Sunitinib	Renal cell	PERK	NF-B pro-survival pathway	Makhov et al. (2018)
	Vemurafenib	Thyroid	PERK	Protective autophagy	Wang et al. (2017)
	Vemurafenib	Melanoma & CRC	GCN2	Increased nutrient transport	Nagasawa et al. (2016)
	Trametinib	FBXW7 deficient	GCN2	Apoptosis inhibition	Sanchez Burgos et al. (2022)

Stress Modulator Platform

Stress Modulator Platform

Stress Modulator Platform

Targeting the Adaptive Stress Response

Disrupting the Stress Response

HC-5404

A UPR Inhibitor

Mechanism of Action

Clinical Development

Fast Track Designation

HC-7366

An ISR Modulator

Mechanism of Action

Clinical Development

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

Stress Modulator
Platform

Stress Modulator
Platform

Stress Modulator
Platform