Table 3.
Structurally characterized allosteric and spanning ATP-allosteric hybrid inhibitors effective against L858R, T790M, and C797S mutants
| Compound Namea | PDB ID | EGFR Kinase Domain αC-helix | Interactions with K745 and D855 | Ref | |
|---|---|---|---|---|---|
| 1 | EAI001 | 5D41 | out | H-bond between aminothiazole and D855, H-bond between AMP-PNP and K745 | (Jia et al., 2016) |
| 2 | EAI002 | 6P8Q | out | H-bond between carbonyl and K745. | (D. J. H. De Clercq et al., 2019) |
| 3 | EAI045 | 5ZWJ | out | H-bond between aminothiazole and D855, H-bond between isoindolinone and K745 | (P. Zhao, Yao, Zhu, Chen, & Yun, 2018) |
| 4 | 6P1L | out | H-bond between aminothiazole and D855, H-bond between AMP-PNP and K745 | (D. J. De Clercq et al., 2019) | |
| 5 | JBJ-09-063 | 7JXQ | out | H-bond between aminothiazole and D855, H-bond between AMP-PNP and K745 | (To, Beyett, Jang, Feng, Bahcall, Haikala, Shin, Heppner, Rana, Leeper, et al., 2022) |
| 6 | JBJ-09-063 | 7K1I | out | H-bond between aminothiazole and D855, H-bond between AMP-PNP and K745. H-bond between L858R and K745 | (Tyler S Beyett, To, et al., 2022; To, Beyett, Jang, Feng, Bahcall, Haikala, Shin, Heppner, Rana, & Leeper, 2022) |
| 7 | JBJ-04-125-02 | 6DUK | out | H-bond between aminothiazole and D855, H-bond between AMP-PNP and K745 | (To et al., 2019) |
| 8 | DDC4002 | 6P1D | out | H-bond between aminothiazole and D855, H-bond between AMP-PNP and K745 | (D. J. H. De Clercq et al., 2019) |
| 9 | Compound 34 (15) | 7LTX | out | H-bond between NH of amide and D855. | (Thomas W Gero et al., 2022) |
| 10 | Compound 38 (16) | 8A2B | out | H-bond between aminothiazole and D855. H-bond between inhibitor ketone and K745 | (Obst-Sander, Ricci, Kuhn, Friess, Koldewey, Kuglstatter, Hewings, Goergler, Steiner, & Rueher, 2022) |
| 11 | Compound 57 (17) | 8A2D | out | H-bond between aminothiazole and D855 | (Obst-Sander, Ricci, Kuhn, Friess, Koldewey, Kuglstatter, Hewings, Goergler, Steiner, & Rueher, 2022) |
| Simultaneously Bound ATP Site TKIs and allosteric inhibitors | |||||
| 12 | AZD9291 and EAI045 | 7JXM | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Tyler S Beyett, To, et al., 2022) |
| 13 | AZD9291 and DDC4002 | 6XL4 | out | H-bond between benzodiazepinone ketone and K745. | (Tyler S Beyett, To, et al., 2022) |
| 14 | AZD9291 and JBJ-04-125-02 | 7JXP | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Tyler S Beyett, To, et al., 2022) |
| 15 | PF-06747775 and JBJ-04-125-02 | 7JXK | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Tyler S Beyett, To, et al., 2022) |
| 16 | AZD9291 and JBJ-09-063 | 7JXW | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Tyler S Beyett, To, et al., 2022) |
| 17 | ASP8273 and JBJ-09-063 | 7LG8 | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Tyler S. Beyett, To, et al., 2022) |
| 18 | AZD9291 and JBJ-09-063 | 7K1H | out | H-bond between aminothiazole and D855. H-bond between isoindolinone ketone and K745. H-bond between L858R and K745 | (Tyler S Beyett, To, et al., 2022) |
| 19 | PF-06747775 and JBJ-04-125-02 | 7JXK | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Tyler S Beyett, To, et al., 2022) |
| 20 | PF-06747775 and EAI001 | 6Z4D | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Niggenaber et al., 2020) |
| 21 | AZD9291 and EAI045 | 6Z4B | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Niggenaber et al., 2020) |
| 22 | Spebrutinib and EAI001 | 7A2A | out | H-bond with aminothiazole and D855. H-bond between isoindolinone ketone and K745. | (Niggenaber et al., 2020) |
a
Note that we have listed all compounds according to their generic name or compound code included in the original reference. We have elected to enumerate all of the compounds here that are reported by numeral in the original reference for clarity.