CONNECT
Let science do the talking
Current
Programs
RUNAWAY
IMMUNE RESPONSE
STING antagonist
Curadev initiated a small molecule STING antagonist program that has yielded novel chemotypes that inactivate STING. The program is developing distinct pharmacophores with potentially distinct mechanism of STING inactivation.
TNIK
Curadev has nominated COMPOUND 6, its lead small-molecule TNIK inhibitor, as a candidate for US FDA IND. The TNIK inhibitor program has yielded potent and selective TNIK inhibitors that alleviate liver fibrosis in murine models. COMPOUND 6 is also in preclinical development for metabolic disorders.
CLK/DYRK DUAL INHIBITOR PROGRAM
Curadev has nominated COMPOUND 9, its lead small-molecule dual CLK/DYRK inhibitor, as a candidate for US FDA IND filing. The dual CLK/DYRK inhibitor COMPOUND 9, a potent and selective dual inhibitor is being developed for the treatment of osteoarthritis by intra-articular (IA) injection.
NEURO
INFLAMMATION
Target Identification Program
Curadev has initiated collaboration at INSERM’s Hôpital Robert Debré in Paris with Professor Pierre Gressens, a leading clinician researcher, who established that microglia driven neuroinflammation was the underlying cause of diverse neuropathologies including perinatal brain injury and white matter damage. This partnership places Curadev at the translational edge of academic research by providing us access to early discoveries on new pathways as well as current thinking in the field of neuro-immunology. Curadev will also have access to several central nervous system derived human and mouse cell lines as well as primary cultures and in-vivo disease models. For Curadev, this collaboration forms an important component of our early stage target identification program in the area of autoimmune diseases and cancers.
IMMUNE
ONCOLOGY
STING agonist
The STING agonist program focuses on kick-starting an innate immune response in tumors which are devoid of a T cell infiltrate and are consequently immunologically silent. Generating a Type I Interferon response in these non-inflamed tumors leads to the activation of CD8α dendritic cells which recruit CD8 T-cells and initiate strong anti-tumor responses. We have designed and developed potent classical small molecule (non-nucleoside) human STING agonists that activate all isoforms of human STING leading to robust secretion of Type I interferons and related cytokines. In order to increase the therapeutic index of our portfolio we have created modular sets of linkers and spacers to enable conjugation of our compounds to peptides and biomolecules.
TDO/IDO
Greater than 90% of ingested tryptophan is metabolized to kynurenine by Tryptophan dioxygenase (TDO2) and Indoleamine 2,3 dioxygenase (IDO1) which are rate limiting oxidoreductase enzymes of the kynurenine pathway (KP). The action of kynurenine and its metabolites and the depletion of local tryptophan levels have immunosuppressive consequences in the tumor microenvironment by subduing active immune responses by creating a tolerogenic tumor microenvironment characterized by increased numbers of circulating regulatory T cells and a decreased number of CD8+ T cells. Elevated kynurenine to tryptophan (K/T) ratios are associated with resistance to checkpoint blockade drugs that target CTLA4 or PD-L1/PD1.
Curadev has discovered potent small molecule enzyme inhibitors that fall into two classes – IDO specific inhibitors and first in class TDO/IDO dual inhibitors. The therapeutic goal is to combine these molecules with other immune check point inhibitors or specific cytotoxic therapies to potentiate immune response against various types of tumors.
Curadev’s lead small molecule drug candidate is a powerful dual inhibitor of TDO and IDO and reduces kynurenine levels in rodents, dogs and primates.
HPK1
High expression of HPK1 (Hematopoietic Progenitor Kinase 1) correlates with reduced patient survival in several cancer types. The small molecule HPK1 inhibitor program attempts to block this kinase from inactivating several types of immune cells. HPK1 driven phosphorylation down regulates signaling by T and B cell receptors, prostaglandins and ligands of the TNF superfamily and plays a regulatory role in turning off nearly every step of an inflammatory immune response. Within the cancer immunity cycle, HPK1 decreases neo-antigen release and presentation, T cell priming and activation, the trafficking and infiltration of T cells into tumors and helps create the immunosuppressive tumor microenvironment that blunts the action of T lymphocytes.
VACCINE
ADJUVANTS
Vaccine Adjuvants Program
Curadev is evaluating the adjuvant potential of potent leads from its IDO/TDO inhibitor and STING agonist platforms to boost T cell independent and T cell dependent vaccine responses. The goal is to identify adjuvant formulations from our internal repository of compounds that boost the performance of commercial vaccines. Respiratory disease vaccines designed to protect against bacterial and viral pneumonia are the first vaccines being evaluated.
ACETATE
METABOLISM
ACSS2
Acetate is directly converted to acetyl CoA by a family of Acyl-coenzyme A synthetase short-chain enzymes (ACSS). Among these, ACSS2 has attracted special interest. There is an increasing body of clinical evidence that places acetate and ACSS2 at a critical metabolic node in tumor cells under nutritional and hypoxic stress. High ACSS2 expression in patients with grade-2/3 gliomas or triple negative breast cancer is associated with shorter overall survival. Infusions of 13C-acetate into the brains of GBM patients with brain tumors has established that almost half of the acetyl-CoA in the tumors originated from acetate and that these tumors expressed moderate to high levels of ACSS2.
Curadev’s ACSS2 program focuses on the ability of tumors to survive in hostile microenvironments by altering their metabolic requirements. We have developed potent small molecule inhibitors of Acyl-coenzyme A synthetase short-chain family member 2 (ACSS2) to target tumor survival in these conditions. Combinations of these inhibitors with other forms of cancer therapy are being investigated to identify synergistic modes of tumor elimination.
Other applications of ACSS2 inhibitors: ACSS2 which plays a role in lipid metabolism could also be targeted in hepatic steatosis to reduce lipid accretion without altering lean body mass.