Session: 802. Chemical Biology and Experimental Therapeutics: Poster II
Hematology Disease Topics & Pathways:
Research, Translational Research, MPN, Drug development, Chronic Myeloid Malignancies, Diseases, Treatment Considerations, Myeloid Malignancies
KT-253, a highly selective MDM2 degrader, is currently being evaluated in clinical trials in high grade myeloid malignancies, solid tumors and lymphomas (NCT05775406). In contrast to MDM2 SMIs that block the p53/MDM2 interaction, KT-253 catalytically degrades MDM2 overcoming the p53-dependent feedback loop that upregulates MDM2. We hypothesized that, MDM2 degradation with KT-253 would be a more effective approach than MDM2 SMIs in eliminating malignant MF HSCs.
Using UKE-1 cells, a p53 WT JAK2V617F+ cell line, KT-253 treatment was shown to lead to >10-fold increase in the degree of cell growth inhibition and apoptosis as compared to the MDM2 SMI AMG-232 (100nM vs 1000nM). KT-253 treatment also led to significant increase in fraction of cells in sub-G1 phase as well as reduction in cells in S and G2/M phases. In contrast, KT-253 had no effect on p53 mutated JAK2V617F+ SET-2 cells indicating that KT-253 induced cell growth inhibition and apoptosis was p53 dependent. Furthermore, treatment of primary MF CD34+ cells with various doses of the KT-253 led to significant reduction of CD34+ cell viability and induction of apoptosis, while 10-40 fold higher concentrations of AMG-232 were required to suppress MF CD34+ cell growth or induce apoptosis to a similar degree. These effects of KT-253 were associated with upregulation of the p53 transcriptional targets p21, NOXA and PUMA.
Treatment of primary MF CD34+ cells at nanomolar concentrations (12.5nM) of KT-253 led to a 60% reduction in hematopoietic colony formation, while this same dose did not affect the colony forming potential of normal CD34+ cells. In contrast, 125nM of AMG-232 treatment led to only 20% reduction in MF hematopoietic colony formation. Since KT-253 is administered intermittently, we also evaluated the effect of a 4-hour exposure of MF and normal donor CD34+ cells to KT-253 followed by a washout period and then assaying hematopoietic colony formation potential. Short term exposure to KT-253 (12.5, 25, 50 and 100nM) significantly decreased MF colony numbers by 30-60 % (p=0.04, p=0.05, p=0.016 and p=0.002, respectively) but had no effect on normal donor colony numbers. By contrast, short term treatment with AMG-232 (125, 250 500 and 1000nM) did not affect either MF or normal colony numbers. Importantly, treatment of MF CD34+ cells with 12.5 nM of KT-253 decreased by 71% the numbers of JAK2V617F+ colonies assayed, while sparing JAK2 WT colonies. By contrast, 125nM of AMG-232 reduced the number of JAK2V617F+ colonies by only 28%, at >10-fold higher concentrations. Selective depletion of malignant MF CD34+ cells by KT-253 strongly suggests that this degrader has a substantial therapeutic window which could eliminate MF CD34+ cells but spare non-mutated CD34+ cells and limit hematological toxicities associated with MDM2 SMI therapy.
In conclusion, KT-253 is a highly potent and effective MDM2 degrader which upregulates p53 activity in MF CD34+ cells and can selectively reduce the numbers of JAK2V617F+ colonies formed while sparing the reservoir of colonies with WT JAK2. These data provide a compelling rationale for evaluating the therapeutic potential KT 253 in MF patients.
Disclosures: Chutake: Kymera Therapeutics: Current Employment, Current holder of stock options in a privately-held company, Other: have stock or stock options. Dey: Presage: Patents & Royalties: self; Kymera: Current Employment, Current equity holder in publicly-traded company. Hoffman: Silence Therapeutics: Consultancy; Protagonist Therapeutics: Consultancy; Karyopharm therapetics: Research Funding; Kymera: Research Funding; Cellenkos: Research Funding; Dexcel: Research Funding.
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