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Design, synthesis and biological evaluation of Nucleosidic CD99 inhibitors that selectively reduce Ewing sarcoma
Kaluvu Balaraman1, Emre Deniz2, Eryn Nelson3
1Chemistry Department, Georgetown University, Washington, DC, 20057, USA; Medicinal Chemistry Shared Resource (MCSR), Georgetown University Medical Center, Washington, DC, USA.
Abstract:
Ewing Sarcoma (ES) is a cancer of bone and soft tissues affecting mostly children and young adults. Aggressive progression and poor prognosis of this malignancy call for novel and targeted treatments. CD99 is a transmembrane protein that is abundantly expressed on ES cells and is a diagnostic marker for the disease. ES cells are selectively sensitive to CD99 inhibition compared to most normal cells and other tumors. Therefore, CD99 is a good molecular target for ES treatment. Clofarabine and cladribine are two FDA approved drugs that are administered for their inhibitory acts on DNA synthesis to treat relapsed or refractory acute lymphoblastic and myeloid leukemia. They have also been shown to directly bind to CD99 and inhibit ES growth through a distinct mechanism. In the current study, we designed, synthesized and tested new ES specific derivatives of both drugs that would continue to target CD99 but with expected reduction in cellular membrane permeability and rendered unsuitable for inhibiting DNA synthesis. By using commercially available clofarabine and cladribine purine nucleoside analogs, we modified the primary alcohol moiety at the deoxyribose C-5' terminal site to suppress phosphorylation and thus inhibition of subsequent DNA synthesis pathways. In addition, we incorporated a variety of polar groups in the ribose and purine rings to reduce membrane permeability and investigated the effects of configurational changes in the sugar moiety. Among 26 new derivatives, we identified two compounds, BK50164 and BK60106, that cause cell death specifically in ES primarily due to inhibition of CD99 but not via inhibition of DNA synthesis. These findings provide a road map for the future development selective CD99 inhibitors for targeted treatment of ES.
Insights
New drug derivatives targeting CD99 show promise for treating Ewing Sarcoma (ES), a rare cancer. These compounds selectively kill ES cells by inhibiting CD99 without affecting DNA synthesis, offering a targeted therapy approach.
Area of Science:
- Oncology
- Molecular Biology
- Medicinal Chemistry
Background:
- Ewing Sarcoma (ES) is a pediatric and young adult cancer with poor prognosis.
- CD99 is a highly expressed protein on ES cells, making it a potential therapeutic target.
- Existing drugs like clofarabine and cladribine inhibit DNA synthesis and also target CD99 in ES.
Purpose of the Study:
- To design and synthesize novel drug derivatives targeting CD99 for ES treatment.
- To create compounds that inhibit CD99 selectively in ES cells.
- To develop ES-specific therapies that do not inhibit DNA synthesis.
Main Methods:
- Modified clofarabine and cladribine analogs by altering the deoxyribose C-5' terminal site to prevent phosphorylation.
- Incorporated polar groups and altered sugar moiety configurations to reduce membrane permeability.
- Synthesized and tested 26 new derivatives for ES cell-specific cytotoxicity.
Main Results:
- Identified two compounds, BK50164 and BK60106, with specific cell-killing activity against ES.
- Demonstrated that these compounds inhibit ES cell death primarily through CD99 inhibition.
- Confirmed that the new derivatives do not inhibit DNA synthesis, unlike parent drugs.
Conclusions:
- Developed novel, selective CD99 inhibitors for Ewing Sarcoma treatment.
- These derivatives offer a targeted therapeutic strategy with reduced off-target effects.
- Findings pave the way for developing new, effective treatments for ES.
