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	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

How We Disrupt the Stress Response

A UPR Inhibitor

Mechanism of Action

Clinical Development

Fast Track Designation

An ISR Inhibitor

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