Anti-Id Platform

Unlocking the Vast Potential of Id Protein Inhibitors

Id Proteins are Implicated in the Progression of Many Diseases

AngioGenex and its collaborators have assembled key anti-Id platform enabling technologies and tools that allow for the identification of specific and potent small molecule binders of Id.

Id proteins are helix-loop-helix (HLH) transcriptional regulators frequently overexpressed in certain cancers. Id protein inhibitors have been proposed as therapeutic targets due to the important role they play in mediating cancer pathogenesis. Id proteins are also implicated in certain disorders of the eye.

Id Protein

Small Molecule Binder Targets Id for Degradation

AngioGenex’s Anti-Id platform gave rise to AGX-A, an investigational small molecule designed to selectively bind to Id proteins, thereby targeting them for degradation and reducing resulting tumor growth and neovascularization.

Id Proteins are Critically Important for Tumor Growth and Other Pathologic Vascular Events

Id proteins were first identified as proteins that controlled the growth and specialization of cells in the early embryo. It was shown that high levels of Id expression were required for cells in the embryo to undergo the appropriate number of rounds of cell division before they began to develop into specialized cells of certain tissues (such as muscle and brain and blood vessels).

The growth of blood vessels at metastatic sites is also under the control of Id proteins. When metastatic tumors begin to grow, they recruit rapidly growing blood vessels that re-express Id proteins. Critically, Id proteins are not expressed in normal “healthy” blood vessels, making them attractive therapeutic targets.

Loss of Id Genes Prevents Blood Vessel Formation in Adult Mice Implanted with Growth Factor VEGF

Normal Mouse (Left) versus Id Knockout Mouse (Right)

Id Binding Site Cannot Mutate and Retain Activity

AGX-A, our lead Anti-Id Platform candidate, is an investigational small molecule designed to selectively bind to ID proteins, partially unravel the ID protein structure and thereby mark them for degradation. Importantly, the pocket to which AGX-A binds is highly conserved throughout evolution and cannot be mutated and retain activity. This, in addition to the potent degradation capacity of AGX-A make acquired resistance to this drug through mutation or amplification of the ID targets very unlikely. Indeed, to date, in preclinical models of cancer, acquired resistance has not been observed.

AGX-A is Predicted to Bind the Highly Conserved Loop Region

AngioGenex researchers analyzed the 3D structure of Id and identified a “crevice” between the a-helices (green) suitable for drugging.

Id Protein

Approach Supported by Preclinical Data

AngioGenex researchers have demonstrated in animal models the ability to deliver a small molecule capable of dramatically reducing Id protein levels with minimal side effects. Preclinical research was conducted on AGX51, a legacy compound.

  • Treatment led to Id protein loss (even when Id is overexpressed) in multiple cancer cell types
  • Treatment was well tolerated and caused no apparent toxicity in mice
  • Treatment decreased the size and number of lung tumor metastases in a breast cancer model
  • Treatment led to a dramatic increase in reactive oxygen species, suggesting potential for cancer-killing activity

Twice Daily AGX51 (Legacy Compound) Inhibits Metastatic Spread with Little Toxicity in a Breast Cancer Mouse Model

Twice daily administration 50 mg/kg ip

Foundational Research Investigating Id

Wojnarowicz PM, et al. Anti-tumor effects of an Id antagonist with no acquired resistance. bioRxiv. 2020;01(06):894840
Wojnarowicz PM, Lima E Silva R, Ohnaka M, et al. A small-molecule pan-id antagonist inhibits pathologic ocular neovascularization. Cell Rep. 2019;29(1):62-75.e7.
Lasorella A, Benezra R, Iavarone A. The ID proteins: master regulators of cancer stem cells and tumour aggressiveness. Nat Rev Cancer. 2014;14(2):77-91.
Stankic M, Pavlovic S, Chin Y, et al. TGF-β-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep. 2013;5(5):1228-1242.
Shaked Y, Henke E, Roodhart JML, et al. Rapid chemotherapy-induced acute endothelial progenitor cell mobilization: implications for antiangiogenic drugs as chemosensitizing agents. Cancer Cell. 2008;14(3):263-273.
Swarbrick A, Roy E, Allen T, Bishop JM. Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. Proc Natl Acad Sci U S A. 2008;105(14):5402-5407.
Henke E, Perk J, Vider J, et al. Peptide-conjugated antisense oligonucleotides for targeted inhibition of a transcriptional regulator in vivo. Nat Biotechnol. 2008;26(1):91-100.
de Candia P, Solit DB, Giri D, et al. Angiogenesis impairment in Id-deficient mice cooperates with an Hsp90 inhibitor to completely suppress HER2/neu-dependent breast tumors. Proc Natl Acad Sci U S A. 2003;100(21):12337-12342.
Benezra R, Rafii S, Lyden D. The Id proteins and angiogenesis. Oncogene. 2001;20(58):8334-8341.

Broad IP Protections Secured

AngioGenex’s proprietary assets include issued and pending patents and the exclusive rights to certain novel small molecule Id protein inhibitors. More details are coming soon.