Project Grant R21CA286412

DISCOVERY OF MAP2K7 INHIBITORS THROUGH DNA-ENCODED CHEMICAL SCREENS TO TREAT T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA - PROJECT SUMMARY ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) IS AN AGGRESSIVE HEMATOLOGICAL MALIGNANCY. THE DISEASE INCIDENCE PEAKS IN CHILDREN YOUNGER THAN FIVE, DECLINING UNTIL THE MID-20S AND INCREASING AFTER AGE 50. DESPITE ADVANCES IN TREATING PEDIATRIC PATIENTS, AT LEAST ONE OUT OF FIVE CHILDREN RELAPSE AND DIE OF LEUKEMIA. T-CELL ALL (T-ALL) PRESENTS A HIGHER RISK FOR RELAPSE THAN THE B-CELL ALL SUBTYPE, AND RELAPSE DISEASE IS A SIGNIFICANT CAUSE OF CANCER-RELATED DEATHS IN CHILDREN. CHILDREN WITH LEUKEMIA EXHIBITING AN INCREASED RISK OF TREATMENT FAILURE AND RELAPSE DESPERATELY NEED AN ALTERNATIVE THERAPY TO INDUCE DURABLE REMISSION. HOWEVER, DEVELOPING ALTERNATIVE TREATMENTS REQUIRES IDENTIFYING ACTIONABLE PRO-LEUKEMIC PATHWAYS IN LEUKEMIC CELLS, PARTICULARLY IN DRUG-RESISTANT LEUKEMIC CELLS ABLE TO REINITIATE DISEASE AND CAUSE RELAPSE. WE ARE WELL-POSITIONED TO FULFILL THIS MEDICAL NEED BECAUSE WE RECENTLY IDENTIFIED ABERRANT ACTIVATION OF THE KINASE MAP2K7 IN BULK T-ALL LEUKEMIC CELLS AND THE LEUKEMIA- INITIATING CELL (LIC) POPULATION INVOLVED IN REFRACTORY AND RELAPSED DISEASE. IN THE ABSENCE OF POTENT AND SPECIFIC INHIBITORS OF MAP2K7, WE SHOWED AS A PROOF OF CONCEPT THAT LEUKEMIC CELLS ARE VULNERABLE TO PHARMACOLOGICAL JNK INHIBITION, THE SOLE DOWNSTREAM TARGET; HOWEVER, LOW POTENCY AND OFF-TARGET TOXICITY PREVENT TRANSLATING JNK INHIBITORS TO THE CLINICS. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT DIRECT TARGETING WITH NOVEL MAP2K7 INHIBITORS CAN INCREASE TREATMENT RESPONSE BY ERADICATING CHEMORESISTANT LEUKEMIC CELLS. IN THIS APPLICATION, WE PROPOSE DEVELOPING TARGETED INHIBITION OF THE ABERRANTLY ACTIVATED MAP2K7 PATHWAY THROUGH THE SCREEN OF MAP2K7 PROTEIN BINDERS USING DNA-ENCODED CHEMICAL LIBRARIES (AIM 1) AND STUDYING KINASE INHIBITORY ACTIVITY AND EFFICACY OF IDENTIFIED INHIBITORS IN PRE-CLINICAL MOUSE MODELS TO ACCELERATE CLINICAL TRANSLATION IN T-ALL PATIENTS (AIM 2). TO ACHIEVE THIS GOAL, WE ASSEMBLED A COLLABORATIVE TEAM COMPOSED OF A RESEARCH SCIENTIST WITH EXPERTISE IN GENETIC AND XENOGRAFT MOUSE MODELS TO STUDY T-ALL, A PHYSICIAN-SCIENTIST INVOLVED IN CLINICAL TRIALS AT THE TEXAS CHILDREN'S HOSPITAL, AND A MEDICINAL CHEMIST AT THE CENTER FOR DRUG DISCOVERY AT BAYLOR COLLEGE OF MEDICINE. THE PROPOSED STUDY CAN RESULT IN NEW THERAPIES TO TARGET A NOVEL TARGET TO TREAT PEDIATRIC PATIENTS WITH HIGH-RISK LEUKEMIA.