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ANovelSmallMoleculeMenin-MLLInhibitorforPotentialTreatmentofMLL-rearrangedLeukemiasTao Wu1, Linda Kessler1, Shuangwei Li1, Trupta Purohit2, Shisheng Li1, Hongzhi Miao2, Brian Linhares2, Rasmus Hansen1, Jeff Kucharski1, Yi Wang1, Ke Yu1, Katarzyna Kempinska2, Tess Ely1, Szymon Klossowski2, AtaZarieh1, Ulf Peters1, Jun Feng1, Yvonne Yao1, Yuan Liu1, Bo Wen2, Francis Burrows3, Duxin Sun2, Jingchuan Zhang1, Levan Darjania1, Dana Hu-Lowe1, Patrick Zarrinkar1, Liansheng Li1, Tomasz Cierpicki2, JolantaGrembecka2, Pingda Ren3, Yi Liu3*. 1Wellspring Biosciences, La Jolla, CA; 2University of Michigan, Ann Arbor, MI; 3Kura Oncology, La Jolla, CA * Corresponding author: [email protected]
IntroductionPatients with MLL-rearranged leukemia typically have a poorprognosis. With chemotherapy and stem cell transplantation ascurrent standard of care, the 5-year survival rate is estimated to be40%. As the leukemogenic activity of MLL fusion proteins has beenshown to be dependent on their direct interaction with menin,development of small molecules that block the menin-MLLinteraction is a promising therapeutic strategy for the treatment ofthis disease.We describe KO-539, a menin-MLL inhibitor with optimized drug-like properties that demonstrates potential clinical utility inpreclinical models of MLL leukemias. The compound is currentlyunder further preclinical evaluation.
Background• MLL-r leukemias are an aggressive type of blood cancer,
predominantly in children and therapy-related leukemia in adults• Chromosomal translocations in the MLL gene at 11q23 result in
MLL fusions with any of more than 50 partner genes• MLL fusion proteins drive leukemogenesis through deregulation
of HOX and MEIS genes• The leukemogenic activity of MLL fusion proteins is critically
dependent on menin binding Conclusions• KO-539 is a highly potent and selective inhibitor of the menin-
MLL interaction• KO-539 demonstrates robust, sustained tumor inhibition in
subcutaneous and disseminated models of MLL-r leukemias;in vivo activity correlates with PD and target gene expressionmodulation
• KO-539 demonstrates acceptable tox profiles and drug-likeproperties
• KO-539 has been selected as a development candidate
• Additional efforts are underway to assess potential utilities ofmenin-MLL inhibitors in additional hematological malignanciesand solid tumor indications
Characterization of the menin-MLL complex
KO-539 is a potent and selective menin inhibitoridentified through structure-based optimizationof a HTS hit
• KO-539 shows good biochemical and cellular activity• KO-539 displays greater than 50-fold selectivity over cell lines
without the MLL fusion
KO-539 demonstrates robust efficacy and adurable response in subcutaneous MV4;11leukemia xenograft model in mice
• Tumor regression was observed at 50 and 100 mpk (oral dosing)• Durable tumor growth inhibition: tumors were undetectable 30
days after cessation of dosing• KO-539 is well tolerated at tested dose levels
Acknowledgements • We thank Shanghai Langtze Biomedical Technology Co, LTD Shanghai,
China for their support on synthesis of menin-MLL inhibitors• We thank Dr. Thomas Look, Dana Farber Cancer Institute, for providing
MV4;11 cells expressing luciferase to the University of Michigan forstudies
Cell Lines with MLL Fusions as drivers (GI50)
Biochemical Assay (IC50)
Murine BM Cell Line (rMLL-AF9)
7 nM MLL(4-43)/Menin Binding
22 nM
MV4;11 (MLL-AF4 AML) 15 nM Control Cell Lines without MLL Fusions (GI50)
MOLM13 (MLL-AF9 AML) 16 nM REH 1.5 µM
KOPN8 (MLL-ENL AML) 20 nM U937 > 6 µMRS4;11 (MLL-AF4 ALL) 23 nM K562 > 6 µM
SEM (MLL-AF4 ALL) 17 nM KG-1 > 4.5 µM
Dose Median Survival Survival BenefitVehicle - 16.5 days -
KO-53925 mpk qd 20 days 3.5 days50 mpk qd 26 days 9.5 days
100 mpk qd 47.5 days 31 days
B. Human CD45+ cell inhibition
KO-539 extends survival in the aggressivesystemic MOLM-13 leukemia model in mice
• KO-539 provides dose-dependent survival benefit in the aggressivedisseminated MOLM13 leukemia model
• The observed survival benefit correlates with human blasts reduction
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KO-539 100mg/kg/qd
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HTS provided starting point
Structure-based optimization
KO-539 (Development
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KO-539 modulates pharmacodynamic (PD)biomarkers in the disseminated MV4;11leukemia model in mice
A. Reduction of luciferase signal B. Reduction of human CD45 in the bone marrow and the spleen
C. Pharmacodynamic activity in the bone marrow (modulation of menin target genes)
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• Dosing initiated 19 days post tumor implantation and continued for6 days
• KO-539 reduces tumor burden relative to the vehicle in the bonemarrow and the spleen
• KO-539 dose dependently modulated expression of menin-MLLassociated PD markers
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v e h ic le
K O -5 3 9 1 0 0 m p k q dK O -5 3 9 5 0 m p k q d
D a y s a fte r tre a tm e n tB o n e m a rro w S p le e n
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V eh ic leK O -5 3 9 5 0 m p k q dK O -5 3 9 1 0 0 m p k q d
B. Tumor burden assessed by flow cytometry at end of 20 day treatment
KO-539 displays survival benefit in thedisseminated MV4;11 leukemia model
Vehicle KO-539 @ 50 mpk bid KO-539 @ 100 mpk qdMean
Survival 41.5 days 67 days 66 days
• KO-539 significantly prolongs mouse survival compared to thevehicle control group
• Survival benefit correlates with reduction of human leukemiablasts (hCD45+) in the mice
A. Survival benefit by KO-539
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v e h ic leK O -5 3 9 5 0 m p k b idK O -5 3 9 1 0 0 m p k q d
T re a tm e n t d a y s 1 6 -3 6
A. Survival benefit by KO-539
