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An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling

ABSTRACT: Insulin and insulin-like growth factors (IGF-1 and IGF-2) regulate metabolism, growth, and development via related receptors. In contexts such as brain function or fetal development, coordinated signaling by all three hormones is essential. We report the engineering of [GluB10, D-HisB24, GlyB31, TyrB32]-insulin (1Ins), an analog with high affinity for IR-A, IR-B, and especially IGF-1R. 1Ins binds IGF-1R ~1,000-fold more strongly than native insulin, approaching IGF-1 levels. CryoEM structures reveal how minimal substitutions in 1Ins enable effective binding to both IR-A and IGF-1R. In neuronal cells, 1Ins robustly activates both IR and IGF-1R pathways, promotes survival, and exceeds native ligands in neuroprotective assays. In vivo, 1Ins regulates glucose effectively in mice and rats. Phosphoproteomic profiling confirms dual pathway activation and identifies targets unique to 1Ins. These findings demonstrate that rational design of dual-receptor agonists can yield potent, versatile ligands with therapeutic promise in metabolic control, neuroprotection, and regeneration.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Jana Brezinova

LAB HEAD: Jiri Jiracek

PROVIDER: PXD067251 | Pride | 2026-04-09

REPOSITORIES: Pride

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			Action	DRS
	20241206_IS_15_1_fosfo.raw	Raw
	20241206_IS_15_2_fosfo.raw	Raw
	20241206_IS_15_3_fosfo.raw	Raw
	20241206_IS_15_4_fosfo.raw	Raw
	20241206_IS_15_5_fosfo.raw	Raw

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Project description:Insulin-like growth factor receptor-1 (IGF-1R) inhibition could be a relevant therapeutic approach in small cell lung cancer (SCLC) given the importance of an IGF-1R autocrine loop and its role in DNA damage repair processes. We assessed IGF-1R and pAkt protein expression in 83 SCLC human specimens. The efficacy of R1507 (a monoclonal antibody directed against IGF-1R) alone or combined with cisplatin or ionizing radiation (IR) was evaluated in H69, H146 and H526 cells in vitro and in vivo. Innovative genomic and functional approaches were conducted to analyze the molecular behavior under the different treatment conditions. A total of 53% and 37% of human specimens expressed IGF-1R and pAkt, respectively. R1507 demonstrated single agent activity in H146 and H526 cells but not in H69 cells. R1507 exhibited synergistic effects with both Cisplatin and IR in vitro. The triple combination R1507-Cisplatin-IR led to a dramatic delay in tumor growth compared to Cisplatin-IR in H526 cells. Analyzing the apparent absence of antitumoral effect of R1507 alone in vivo, we observed a transient reduction of IGF-1R staining intensity in vivo, concomitant to the activation of multiple cell surface receptors and intracellular proteins involved in proliferation, angiogenesis and survival. Finally, we identified that the nucleotide excision repair pathway (NER) was mediated after exposure to R1507-CDDP and R1507-IR in vitro and in vivo. In conclusion, adding R1507 to the current standard Cisplatin-IR doublet reveals remarkable chemo- and radiosensitizing effects in selected SCLC models and warrants to be investigated in the clinical setting. We used microarrays to investigate the effect of IGF-1R targetting on the global gene expression. Gene expression data from H526 xenografts under various treatment and time conditions Total mRNA from 33 NCI-H526 SCLC (small-cell lung cancer) xenografts was hybridized to Affymetrix HGU133 Plus 2.0 expression arrays. Log2 gene expression values were calculated using RMA. (A) To identify the molecular mechanisms involved in the response to R1507 alone along the treatment time, we performed global gene expression profiling in H526 xenografts at the following time points: baseline (vehicle), R1507 day 1 and R1507 day 7. (B) To identify the molecular mechanisms involved in the response to CDDP- and IR-R1507 combinations, we performed global gene expression profiling on mice bearing H526 xenografts treated with the following treatment conditions: vehicle, R1507 CDDP, IR, CDDP-R1507 and IR-R1507.

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An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling

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