Mechanism of activation and the rewired network: New drug design concepts

Nussinov R., Zhang M., Maloney R., Tsai C., YAVUZ B. R., TUNÇBAĞ N., ...Daha Fazla

MEDICINAL RESEARCH REVIEWS, cilt.42, sa.2, ss.770-799, 2022 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Derleme
  • Cilt numarası: 42 Sayı: 2
  • Basım Tarihi: 2022
  • Doi Numarası: 10.1002/med.21863
  • Dergi Adı: MEDICINAL RESEARCH REVIEWS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, EMBASE, MEDLINE
  • Sayfa Sayıları: ss.770-799
  • Anahtar Kelimeler: cancer network, driver mutations, drug discovery, inhibitor, kinases, KRAS, K-Ras4B, ONCOGENIC K-RAS, ENERGY LANDSCAPE, FOLDING FUNNELS, CONFORMATIONAL ENSEMBLES, SMALL MOLECULES, TARGETING KRAS, SITE IDENTIFICATION, TISSUE-SPECIFICITY, CRYSTAL-STRUCTURE, BINDING CASCADES
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same-allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure-based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor-specific network, ushering innovative considerations in precision medicine.