Project description:Renneville A, Gasser JA, Grinshpun DE , Jean Beltran PM, Udeshi ND, Dr. Mary E. Matyskiela , Clayton T, McConkey M, Viswanathan K, Tepper A, Guirguis AA, Sellar RS, Cotteret S, Marzac C, Saada V, de Botton S, Kiladjian J, Cayuela J, Rolfe M, Chamberlain PP, Carr SA, Ebert BL. 2021.
Thalidomide analogs exert their therapeutic effects by binding to the CRL4CRBN E3 ubiquitin ligase, promoting ubiquitination and subsequent proteasomal degradation of specific protein substrates. Drug-induced degradation of IKZF1 and IKZF3 in B-cell malignancies demonstrates the clinical utility of targeting disease-relevant transcription factors for degradation. Here, we found that avadomide (CC-122) induces CRBN-dependent ubiquitination and proteasomal degradation of ZMYM2 (ZNF198), a transcription factor involved in balanced chromosomal rearrangements with FGFR1 and FLT3 in aggressive forms of hematologic malignancies. The minimal drug-responsive element of ZMYM2 is a zinc-chelating MYM domain and is contained in the N-terminal portion of ZMYM2 that is universally included in the derived fusion proteins. We demonstrate that avadomide has the ability to induce proteasomal degradation of ZMYM2-FGFR1 and ZMYM2-FLT3 chimeric oncoproteins, both in vitro and in vivo. Our findings suggest that patients with hematologic malignancies harboring these ZMYM2 fusion proteins may benefit from avadomide treatment.
Project description:Development of novel PI3Ks inhibitors is an important strategy to overcome their resistance and poor tolerability in clinical trials. The quassinoid family member Brusatol shows specific inhibitory activity against hematologic malignancies. However, the mechanism of its anti-cancer activity is unknown. We studied the anti-cancer activity of Brusatol on multiple hematologic malignancies derived cell lines by RNA-Seq, mass spectrometry, biochemical pull-down assays, and CRISPR/Cas9 gene knock-out. We demonstrated that the PI3Kgamma isoform was identified as a direct target of Brusatol, and inhibition was lost on PI3Kgamma deficient cells. Novel synthetic analogs were also developed and tested in vitro and in vivo. They shared superior potency in their ability to inhibit malignant hematologic cell lines, and in a xenograft transplant mouse model. They also had minimal toxicity to normal human cells. These new analogs have enhanced potential for development as a new class of PI3K inhibitors for treatment of hematologic malignancies.