The structures of approved macrocyclic drugs and investigating macrocyclic compounds for cancer therapy.

(A) Macrocyclic compounds to target cancer development. Compounds 1–2: macrocyclic peptide drugs for somatostatin receptors; compound 3: inhibitor of RNA-polymerase II; compounds 4–6: Three approved macrocyclic inhibitors for mTORC1; compound 7: microtubule inhibitor; compound 8: HDAC inhibitor; compound 9: JAK2 inhibitor; compound 10: pacritinib analog for JAK2 inhibition; compound 11: pacritinib analog for inhibition of kinase-like CDK9. (B) Macrocyclic compounds to target drug resistance in cancer-targeted therapy. Compound 12: the third generation of approved ALK inhibitor against ALK-resistant mutations; compound 13: a proposed fourth generation of ALK kinase inhibitor drugs that are potent to inhibit multiple lorlatinib-resistant ALK mutants; compounds 14–15: NTRK inhibitors that are effective for NTRK drug-resistant mutants; compound 16: a potential 4th generation of EGFR inhibitors that is potent in inhibiting C797S compound mutations; compound 17: a macrocyclic inhibitor 3f that is highly selective to EGFR mutant proteins but lacks activities to wild type EGFR. Black: approved macrocyclic drugs for disease; Blue: macrocyclic compounds with anticancer activities under clinical or preclinical investigations. CDK, cyclin-dependent kinase; HDAC, histone deacetylase; JAK, Janus kinase; mTORC1, mTOR complex 1; NTRK, neurotrophin receptor kinase.

Cancer is a worldwide leading cause of cancer-related death due to a lack of efficient disease control by drugs. With the increasing unmet needs in cancer treatment, developing novel effective cancer drugs is in great demand. Macrocyclic molecules represent a group of drug molecules with a cyclic skeleton which endows them with unique drug properties such as improved bioavailability, enhanced metabolic stability, increased binding affinity, and favorable pharmacokinetics parameters. The Food and Drug Administration (FDA) has approved a bunch of macrocyclic drugs to treat cancer patients. However, the importance of such molecules in cancer drug development remains underestimated. Recent studies support that macrocyclic molecules can also serve as an effective strategy to overcome drug resistance in cancer treatment, but is a lack of review. The purpose of this manuscript was to provide shreds of evidence on the applications of macrocyclic molecules for cancer therapy: (1) act as cancer drugs to target different proteins critical for cancer development; (2) act as cancer drugs to target resistant mutants of oncogenes to overcome drug resistance in targeted therapy. This review will help to attract more interest in developing macrocyclic drugs for cancer therapy and potentially provide more novel strategies to benefit cancer patients and society.

Article Access: https://doi.org/10.1002/mog2.50

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