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Discovery of novel potent triple IKZF1/2/3 degraders for the treatment of hematological cancers

ABSTRACT: Through subsequent investigations into structure-activity relationships (SAR) and protein degradation mechanisms, we developed a novel and highly effective candidate, MGD-22, demonstrates potent inhibition of hematological cancer growth across a broad range of models and overcame acquired resistance to IMiDs.

ORGANISM(S): Homo Sapiens

SUBMITTER: Weijie Qin

PROVIDER: PXD059572 | iProX | Wed Jan 08 00:00:00 GMT 2025

REPOSITORIES: iProX

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Project description:We investigated the relationships of the two immune-regulatory plant metabolites salicylic acid (SA) and pipecolic acid (Pip) in the establishment of plant systemic acquired resistance (SAR) in Arabidopsis thaliana induced by the bacterial pathogen Pseudomonas syringae. To characterize the transcriptional SAR response, we used wild-type Col-0 plants, SA-deficient sid2 plants and Pip-deficient ald1 plants and performed RNA-sequencing analyses (Bernsdorff et al., Plant Cell, 2016). SAR establishment in the wild-type is characterized by a strong transcriptional response systemically induced in the foliage that prepares plants for future pathogen attack by pre-activating multiple stages of defense signaling. Whereas systemic Pip elevations are indispensable for SAR and necessary for virtually the whole transcriptional SAR response, a moderate but significant SA-independent component of SAR activation and SAR gene expression is revealed. Arabidopsis thaliana plants were grown individually in pots containing a mixture of soil, vermiculite and sand (8:1:1) in a controlled cultivation chamber with a 10-h day (9 AM to 7 PM; photon flux density 100 mol m-2 s-1) / 14-h night cycle and a relative humidity of 70 %. Day and night temperatures were set to 21C and 18C, respectively. Experiments were performed with 5- to 6-week-old, naive plants exhibiting a uniform appearance. To activate SAR, plants were infiltrated between 10 AM and 12 AM into three lower (1) leaves with suspensions of the bacterial pathogen Pseudomonas syringae pv. maculicola (OD600 = 0.005). Infiltration with 10 mM MgCl2 served as the mock-control treatment. Upper (2) leaves were harvested 48 h after the primary treatment for the determination of systemic gene expression by RNA-seq analyses. Three biologically independent, replicate SAR induction experiments were performed with Col-0 and sid2 plants (experimental set 1), and three other biologically independent experiments with Col-0 and ald1 plants (experimental set 2). In each SAR experiment, at least 6 upper (2) leaves from 6 different plants pre-treated in 1 leaves with Psm (MgCl2) were pooled for one biological Psm- (mock-control) replicate. In this way, 3 biologically independent, replicate samples per treatment and plant genotype were obtained within each SAR set.

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Discovery of novel potent triple IKZF1/2/3 degraders for the treatment of hematological cancers

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