Structure-guided expansion strategy unveils potent allosteric SHP2 inhibitors with synergistic efficacy against AML...

Area of Science:

• Oncology
• Pharmacology
• Structural Biology

Background:

• SHP2 phosphatase is a key driver in cancers via RAS-MAPK, PI3K-AKT, and JAK-STAT pathways.
• Allosteric SHP2 inhibitors offer advantages over orthosteric agents by stabilizing the autoinhibited conformation.
• Further optimization is needed to improve the potency, selectivity, and clinical efficacy of SHP2 inhibitors.

Purpose of the Study:

• To design and synthesize novel, next-generation allosteric SHP2 inhibitors.
• To evaluate the enzymatic activity, pharmacokinetic properties, and oral bioavailability of new compounds.
• To investigate the therapeutic potential of dual SHP2 and MCL-1 targeting in acute myeloid leukemia.

Main Methods:

• Structure-guided drug design utilizing detailed profiling of the SHP2 allosteric pocket.
• Systematic optimization of a pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one scaffold.
• In vitro enzymatic assays, pharmacokinetic studies, and in vivo efficacy studies in acute myeloid leukemia models.

Main Results:

• Compounds B1 and B8 achieved nanomolar enzymatic inhibition (IC50 = 39 nM and 15 nM, respectively).
• Compounds B1 and B8 demonstrated acceptable pharmacokinetics and potential for oral bioavailability.
• Compound B8 exhibited significant synergy with the MCL-1 inhibitor VU661013 in preclinical AML models.

Conclusions:

• Rational design strategies can yield potent and orally bioavailable allosteric SHP2 inhibitors.
• Dual targeting of SHP2 and MCL-1 presents a promising therapeutic approach for acute myeloid leukemia.
• This study provides a foundation for developing combinatorial regimens to improve outcomes in high-risk cancers.