DWRX6002 : Potent Androgen/Progesterone Receptor Dual-Degrader (PROTAC) with Enhanced Catalytic & Pharmacologic Properties

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• Androgen(A) is the most fundamental cause of hormonal acne. It induces inflammation and cellular

• Progesterone (P) is suspected to induce menstrual flare caused by hormonal imbalance in females. It is known to stimulate sebaceous cells in a similar way to androgens.

• Estrogen(E) acts in opposition to androgens and progesterone. It inhibits lipid secretion and slows the proliferation of sebaceous gland cells. Hormonal therapies are often given to patients with acne in forms of contraceptives.

• Receptors for these hormones are classified as type 1 nuclear receptors. These receptors differ greatly in terms of how they contribute to acne, but have high structural similarity which poses a problem to conventional small molecule inhibitors.

• DWRX6002 is a highly selective and potent AR/PR dual degrader that degrades pathogenic hormone receptors in acne while leaving estrogen receptors and other mitigating factors untouched,

Diabetic retinopathy (DR) is a microvascular eye disease that occurs in the retina as a diabetic complication. It is one of the leading causes of blindness in the world. Its incidence rate correlates with the duration of diabetic condition and reaches about 60-70% upon 15 years.

DR is a retinal vasculopathy involving a vicious cycle of microaneurysms, blood vessel leakage, and neovascularization. The release of hard exudates and hemorrhage from the vessels cause the retina to thicken and eventually leads to diabetic macular edema(DME) which subsequently damages the optic nerve to cause a gradual loss in vision.

Current treatments for DR/DME are largely limited to intravitreal injections containing anti-VEGF antibodies, representatively known as LUCENTIS® (ranibizumab) and EYLEA® (aflibercept). These products are usually prescribed in parallel to laser and surgical treatments. While the anti-VEGF IVT injections are known to be safe and provide varying treatment response rates, they are highly disfavored due to their invasiveness and high treatment costs.

DWRX2008 is a self-administrable eyedrop solution containing a first-in-class small molecule inhibitor for diabetic retinopathy and macular edema. Unlike antibody eye injections, its mechanism of action is not limited to inhibiting angiogenetic factors such as VEGF, but also normalizes the dysfunctional energy metabolism in the diabetic eye to address a fundamental pathogenic cause. Unlike traditional eyedrop products, DWRX2008 incorporates our proprietary formulation technology to maximize drug delivery to the posterior eye.

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What is AML?

• Acute Myeloid Leukemia is a cancer that develops in the myeloid hematopoietic stem cells. It results in proliferation and accumulation of abnormal blood cells , decreased immunity and internal bleeding.

• Approximately 60% of leukemia patients have AML. About 30% of AML patients have one or more form of FLT3 mutations in which the receptor is constitutively active. About 70% of them have an ITD mutation that correlates with poor prognosis.

• The post-CR recurrence rate following first-line treatment was 50%, while the average 5-year survival rate is approximately 12.6%

• Currently approved FLT3-ITD inhibitors are showing limited improvement in AML patients due to various resistance mechanisms including a new gatekeeper mutation.

• Possibility of rapid approval after phase 2 clinical trial due to drug resistance issue of the only FLT3-ITD approved treatment

• In 2021, the number of newly diagnosed AML patients was 20,000, with a death toll of 11,000.

Development Background

• Developing a drug that can address both original and new combinations of FLT3 mutations in AML patients for higher CR and survival rates.

• Developing a drug that can address microscopic residual disease(MRD) which is responsible for relapse and adaptive mutations

Weakened binding ability to type2 FLT3 inhibitors due to TKD mutation

[Type1 vs. Type2 FLT3 inhibitor] Source: Blood Adv. 24 Mar 2020; 4(6): 1178–1191

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