<span class="paragraphSection"><div class="boxTitle">Abstract</div>We report that the kinase inhibitor Palbociclib is a very low nanomolar ligand for the HIV-1 TAR, a paradigmatic ‘difficult-to-drug’ RNA. Binding is exquisitely specific, since simple chemical modifications of the small molecule, single nucleotide substitutions, or base pair inversions abolish high affinity binding, and is independent from kinase inhibition. Palbociclib also inhibits recruitment of the super elongation complex (SEC) at low nM concentration, the long-standing aim of Tat-TAR targeting efforts. Thus, we demonstrate that low nM affinity, specificity, and potent biochemical activity against ‘undruggable’ RNAs can be readily found within the chemical space of drugs. The structural basis for binding and biochemical activity is demonstrated in the accompanying manuscript.</span>