AACR 2021: Is Novel IKZF1/3 Degrader Active Against Multiple Myeloma?
Posted: Friday, April 16, 2021
At the American Association for Cancer Research (AACR) Annual Meeting 2021, James A. Henderson, PhD, Senior Director, Chemistry, of C4 Therapeutics, Watertown, Massachusetts, and colleagues presented their preclinical research on CFT7455—a novel Ikaros family zinc finger protein 1 and 3 (IKZF1/3) degrader optimized for high-affinity cereblon binding and in vivo efficacy—in the treatment of immunomodulatory drug–resistant multiple myeloma xenograft models (Abstract LB007). Their results suggest that further investigation of CFT7455 as a future therapeutic for patients with myeloma is warranted, and a phase I/II clinical study is planned to start sometime this year.
CFT7445 demonstrated an 800- to 1,600-fold improvement in cereblon binding compared with pomalidomide in biochemical and cellular assays, respectively. CFT7445 influenced more than 75% degradation of IKZF1 in H929 multiple myeloma cells within 1.5 hours. This catalytic degrader’s high-binding affinity allowed antiproliferative activity across many multiple myeloma cell lines, including H929 cells that were resistant to immunomodulatory drugs.
Interferon regulatory factor 4 protein levels declined over 1 week when CFT7455 was administered daily, the investigators reported. When switching from pomalidomide treatment over to CFT7455 on day 18, 67% of animals displayed a tumor regression by day 28, and 100% demonstrated shrinkage on day 35. An H929 tumor xenograft model showed tumor regression after daily administration of CFT7455 at 0.1 mg/kg. Dosing was discontinued after 29 days, but half the tumors stayed below their initial tumor volume by day 63.
Finally, the investigators reported that the combination of CFT7455 and dexamethasone in an RPMI-8226 tumor xenograft model might prove beneficial in terms of survival outcomes for mice bearing RPMI-8226 xenograft tumors, compared with either agent alone.
Disclosure: All study authors are employed by C4 Therapeutics, the manufacturer of CFT7455.