Drugging the undruggable: a computational chemist's view of KRASG12C

Abstract

In recent years, the emergence of targeted covalent inhibitors which bind to the G12C mutant of KRAS have offered a solution to this previously intractable target. Inhibitors of KRAS^G12C tend to be structurally complex, displaying features such as atropisomerism, chiral centres and a reactive covalent warhead. Such molecules result in lengthy and challenging syntheses, and as a consequence critical decisions need to be made at the design level to maximise the chances of success. Here we take a retrospective look into how computational chemistry can help guide and prioritise medicinal chemistry efforts in the context of a series of conformationally restricted tetracyclic quinolines.

Fig. 1. The chemical structures of sotorasib (1-AMG-510), adagrasib (2-MRTX-849) and the focus of this work, 3.

Fig. 2. Compound 4 (orange) crystallised in KRAS^G12C in the presence of GDP (PDB 6T5V). Three key regions were identified for modifying the potency; around the quinazoline–piperazine torsion, around the quinazoline–indazole torsion and targeting a water in proximity to the piperazine.

Fig. 3. Overlay of the four minima found around the quinazoline–piperazine torsion. The three grey minima do not place the acrylamide in the correct vector to target Lys16 and Cys12 – something which is only achieved in the yellow torsion.

Fig. 4. Evolution of the literature KRAS^G12C inhibitor 4 to the first tetracyclic derivatives disclosed in ref. .

Fig. 5. QM derived rotational barriers as a function of dihedral angle and the subsequent implications for separation. It was found that a barrier of >21 kcal mol⁻¹ led to stable atropisomers which did not interconvert.

Fig. 6. The four tetracyclic analogues of 6 prioritised by FEP and synthetic planning.

Fig. 7. The optimisation of 11 to the conformationally restricted 3.

Fig. 8. The distribution and energy (kcal mol⁻¹) of bioactive and non-bioactive states as a function of methylation. Unsubstituted piperazines were found to exist as a roughly 1 : 1 mixture of bioactive and non-bioactive states, whilst the R and S enantiomers favoured the bioactive and non-bioactive forms respectively. The bioactive conformation was defined as the acrylamide being fixed in the requisite position for binding, shown as the blue box in the middle panel.