molecules of the month


mTORC1-selective bi-steric mTOR inhibitor

QW IP activity in xeno., 5552 in Ph. I for cancer

from linking of rapalog + mTOR inh. + opt

Nature Chemical Biology

Revolution Medicines, Redwood City, US

1 min read

3. The Revolution Medicines selective mTORC1 complex inhibitor, RMC-4529, is a bi-steric inhibitor that has a rapamycin-derived, FKBP12-recruiting allosteric mTOR inhibitor covalently linked to an active-site (orthosteric) inhibitor of the mTOR kinase. By inhibiting both binding sites of mTOR, >30-fold selectivity for the mTORC1 complex over mTORC2 complex was found, whereas selective inhibition with mono-steric inhibitors has been hard to achieve. Selective inhibitors of mTORC1 has been desirable since mTORC2 inhibition can lead to hyperglycemia and counterproductive effects in cancer settings, but selective inhibition between complexes which employ the same kinase (mTOR) has been a longstanding challenge. Interestingly, improved selectivity was ultimately found by reducing the independent affinity of each moiety for their respect target sites (FKBP12/FRB or active site).…

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