Abstract
Myc (avian myelocytomatosis viral oncogene homolog) represents one of the most sought after drug targets in cancer. Myc transcription factor is an essential regulator of cell growth, but in most cancers it is overexpressed and associated with treatment-resistance and lethal outcomes. Over 40 years of research and drug development efforts did not yield a clinically useful Myc inhibitor. Drugging the “undruggable” is problematic, as Myc inactivation may negatively impact its physiological functions. Moreover, Myc is a disordered protein that lacks effective binding pockets on its surface. It is well established that the Myc function is dependent on dimerization with its obligate partner, Max (Myc associated factor X), which together form a functional DNA-binding domain to activate genomic targets. Herein, we provide an overview of the knowledge accumulated to date on Myc regulation and function, its critical role in cancer, and summarize various strategies that are employed to tackle Myc-driven malignant transformation. We focus on important structure-function relationships of Myc with its interactome, elaborating structural determinants of Myc-Max dimer formation and DNA recognition exploited for therapeutic inhibition. Chronological development of small-molecule Myc-Max prototype inhibitors and corresponding binding sites are comprehensively reviewed and particular emphasis is placed on modern computational drug design methods. On the outlook, technological advancements may soon provide the so long-awaited Myc-Max clinical candidate.
Highlights
Over 40 years have passed since the discovery of MYC, a major oncogene that is estimated to contribute to at least 75% of all human cancers, including prostate, breast, colon and cervical cancers, myeloid leukemia, lymphomas, small-cell lung carcinomas, and neuroblastoma, among others, most of which are aggressive and respond poorly to the current therapies [1] (Figure 1)
The deregulation of Myc has been linked to most human cancers, making this bona fide oncogenic transcription factor a high-value target for therapeutic intervention
We summarized the efforts that were undertaken to tackle Myc-driven malignant transformation and overcome cancer addiction to this major oncogene
Summary
Over 40 years have passed since the discovery of MYC, a major oncogene that is estimated to contribute to at least 75% of all human cancers, including prostate, breast, colon and cervical cancers, myeloid leukemia, lymphomas, small-cell lung carcinomas, and neuroblastoma, among others, most of which are aggressive and respond poorly to the current therapies [1] (Figure 1). The comparison between the protein-DNA interfaces of Omomyc of Jung et al [80] to that of the Myc-Max DNA complex of Nair et al [75] demonstrated that both complexes bind to the DNA major groove with alike-formed scissor structures at the E-box, and that the basic region of both complexes assume the same phosphate-backbone and base-specific contacts with DNA. These contacts recapitulated the three invariant residues His, Glu, and Arg at positions 12, 16, and 20 in Omomyc as critical DNA recognition points. FiguFrieg4u.re(T4o.p(T) oMpu) lMtipullteipsleeqsueeqnuceenaceligalnigmnemnetnotfotfhtehbeabsaisci,ch, ehleilxix-l-olooopp-h-heelliixx,,lleeuucciinnee zziippppeerr ((bbHHLLHHLLZZ)) domdaoinmsaoinf sseolfecsteeledctmedemmbeemrsbeorfstohfetMheyMc/yMc/aMxa/xM/Maaddnneetwtwoorrkk..MMyyccaanndd MMaaxx mmoonnoommeerrss sshhaarree ~~6600%% simislaimritilyaraittythaet tphreotperiontelienvelelvienl tihnetihrebirHbLHHLLHZLdZodmomaianisn.sS. eSqequueenncceeccoonnsseerrvvaattiioonnss aammoonnggMMyycc,,MMaaxx, , and aMnaddMpardotperiontseianrse abroexbeodxeadndanhdighhilgihglhigtehdteudsuinsigngthtehesasmameecocololorirninggsscchheemmee aass iinn tthhee sscchheemmaattiiccooff the btHheLbHHLLZHdLoZmdaoimn aaitnthatetthoept.oCp.oCnosenrsvearvtiaotnioannaonmomalaielisesbebtewtweeenenththeebbHHLLHHLLZZ ddoommaaiinnss ooff MMaaxxaanndd MadMfamd iflaymrielylarteivlaetitvoetthoeththertehereMe yMc ypcapraalroaglosg[s84[8]4a]raereinidnidciactaetdedwwitihthaassttaarr((**)) bbeellow the mmuullttiippllee alignamligennmt.eGntr.eGenredenotds ointsdiincdaticeacteritcirciatilcaDlNDANArecreocgongintiotinonrerseisdiduueesswwhhilielerreeddddoottss iinnddicate immppoorrttaanntt dimedriimzaetriioznatrieosnidrueseisdmueustmatuedtaitnedOimn Oommyocm. y(Bc.o(tBtomtto)mA)vAaivlaabillaebXle-rXa-yrasytrsutcrtuucrteusreosf ocfocmopmlepxleexsebsobuonudndto the ctaontohneiccaanl oEn-bicoaxl ED-NboAx DreNcoAgrneictioognnsiteiqonuesneqceu:eMncye:cM-Myacx-M(PaDx B(PIDDB: I1DN:K1NP,K1P.8, 1Å.8rÅesorelustoiolunt)i,oMn)a,dM-Mada-x (PDBMIaDx: (1PNDLBWID, 2: 1ÅN)L, MWa, x2-ÅM)a, xM(aPxD-MB aIxD:(P1DABNI2D, :21.9AÅN)2,,a2n.9dÅO)m, aonmd yOcm(PoDmBycID(P:D1B5I0ID, 2: .175IÅ0,).2D.7imÅe).r assembly occurs through the helix-loop-helix (HLH) and leucine zipper (LZ) regions, while DNA binding takes place mainly through the basic (b) region and extends into the HLH region
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