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, and induces sebaceous gland cell proliferation and sebum production.

• Progesterone (P) is the cause of acne caused by hormonal imbalance during the female menstrual cycle, and is known to stimulate sebaceous gland cells to increase sebum production.

• Estrogen € acts opposite to androgens, inhibits fat (sebum) production and slows the proliferation of sebaceous gland cells, is also used to treat acne (contraceptives), and is also inhibited by progesterone.

• The receptors that the above hormones act on (steroid hormone receptors; AR, PR, ER, GR) are all classified as Type 1 nuclear receptors, and the effects of specific hormones on acne are different, but the receptors have a high structural similarity. Therefore, it is known that it is difficult to secure target selectivity with small molecule drugs.

• DWRX6002 is a high selective AR/PR dual degrader that degrades androgen/progesterone receptors, which are acne aggravating factors, but does not degrade estrogen receptors, which are acne mitigating factors.

What is AML?

• 65% of leukemias are AML (acute myeloid leukemia), 30% of which have FLT mutations, and 70% of them have ITD mutations

• A cancer that develops in myeloid hematopoietic stem cells, mainly in elderly adults

• Normal bone marrow function is paralyzed, resulting in accumulation of abnormal cells, decreased immunity, and bleeding

• The recurrence rate after reaching complete remission with first-line treatment was 50%, and the survival rate within 5 years thereafter was 12.6%.

• 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 new AML diagnosed patients will be 20,000, and the number of deaths will be 11,000

• The number of patients with AML is expected to increase by 2.51% annually to exceed 90,000 in 2029

• Asia, where there are many aged societies, has the highest rate of increase in incidence in the world at 3.54% per year.

Therapeutic drug development background

• 30% of AML cases are FLT3 mutation cases, of which 75% are carriers of the ITD mutation. When FLT3 is mutated, the receptor is continuously activated and abnormal bone marrow cells proliferate.

• Secondary and tertiary mutations after ITD show resistance to drug treatment, so there is a high need for new treatments.

• Improving low survival rate and CR attainment in chemotherapy refractory/incompatible mFLT-AML patients

• Treatment of microscopic residual disease (MRD) leading to relapse

• In case of recurrence, it is necessary to respond to the strengthening of resistance to existing treatments

• Overcome mutation (F691L/gatekeeper) resistance to Gilteritinib, the leading product

Type1 inhibitor

• Weakened binding ability to type2 FLT3 inhibitors due to TKD mutation

• Need to develop Type 1 inhibitors capable of responding to ITD/TKD 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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Diabetic retinopathy (DR) is an eye disease in which the microvessels in the retina are damaged, and is a complication of diabetes that accounts for a very high proportion of the causes of blindness in countries around the world. The incidence rate increases as the history of diabetes increases, and reaches about 60-70% in the case of around 15 years.
When continuous blood vessel leakage and accumulation of foreign substances reach the macula at the center of the retina, the thickness of the retina increases and diabetic macular edema (DME) occurs as a complication, which is the main cause of damage to the optic nerve connection and progressive visual loss.
Currently, the standard treatment for DR/DME is an anti-VEGF antibody injection administered intravitreally (IVT), representatively LUCENTIS® (ranibizumab) and EYLEA® (aflibercept). Anti-VEGF antibody injection is prescribed most basically, and laser or surgical treatment is flexibly performed according to intraretinal lesions confirmed through regular checkups. Because of the invasiveness and cost burden of existing treatments, it is urgent to develop new treatments with high compliance and accessibility. DWRX2008 is a first-in-class diabetic retinopathy that normalizes the abnormal energy metabolism process in the posterior part of the eyeball and can deliver the drug to the posterior part of the eyeball in the form of eye drops, unlike most existing treatments that inhibit angiogenesis by inhibiting VEGF. it is a cure

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