{"id":17041,"date":"2022-09-06T10:50:03","date_gmt":"2022-09-06T10:50:03","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/blog\/oncology-drug-discovery-current-trends\/"},"modified":"2022-09-06T10:50:03","modified_gmt":"2022-09-06T10:50:03","slug":"oncology-drug-discovery-current-trends","status":"publish","type":"blog","link":"https:\/\/www.sygnaturediscovery.com\/fr\/blog\/oncology-drug-discovery-current-trends\/","title":{"rendered":"Oncology drug discovery: reflections on current trends"},"content":{"rendered":"

This year\u2019s American Association for Cancer Research (AACR) Annual Meeting in April saw a welcome return to the\u00a0face-to-face format.\u00a0 Some of the <\/span>Sygnature<\/span> Discovery team made the trip to New Orleans to see what\u2019s been happening in the oncology\u00a0drug discovery ecosystem since the last in-person meeting in Atlanta back in 2019.\u00a0 As other cancer science meetings also return to the face-to-face format, the <\/span>Sygnature<\/span> Discovery team have taken the opportunity to reflect on some of the key oncology drug discovery topics that have caught their attention in recent meetings\u2026<\/span><\/span>\u00a0<\/span><\/strong><\/span><\/p>\n

\u00a0<\/p>\n

40 years on from KRAS: Is it time to retire the term<\/span> \u2018undruggable\u2019<\/span>?<\/span><\/strong><\/h2>\n

This year\u2019s AACR meeting coincided with the 40th anniversary of the discovery of KRAS as the first human oncogene. This was celebrated in a special session, which was chaired by Patricia LoRusso. The session included talks from Mariano Barbacid, Frank McCormack and Kevan Shokat all of whom have made significant contributions to the KRAS story. It was very interesting to hear the historical perspective, from the initial identification of KRAS as an oncogene, to the years of basic research untangling its complex biology and finally to the more recent success in drugging this, once considered \u201cundruggable\u201d, target. \u00a0<\/span><\/p>\n

This nicely set the scene for a wealth of presentations and posters around the various methods now being employed to inhibit this key oncogene and the signalling pathways it drives, in the clinic.\u00a0 The advances here perhaps point to a wider frameshift in our thinking around the concept of \u201cundruggable\u201d.\u00a0<\/span><\/p>\n

Given the nature of KRAS and its high affinity for GTP, approaches toward more traditional active site inhibitors were largely dismissed.\u00a0 Through imaginative thinking and synthetic creativity, the new realm of covalent KRAS inhibitors, targeting the key G12C mutation, have emerged, evolved and are now demonstrating clinical benefit.\u00a0<\/span><\/p>\n

However, once more, the expectation was that other KRAS family members would remain intractable.\u00a0 And yet, at the meeting, we saw significant advances toward truly pan-RAS inhibition, either through direct interaction or through binding partners such as SOS1 or Shp2.\u00a0 Seemingly, the once undruggable KRAS has now been conquered.\u00a0 This hard-fought success builds on the determined efforts in the early 1990s to turn kinases from an assumed undruggable protein family into pivotal first-line therapeutics for many patients.\u00a0 And now helicases, again heralded as undruggable, are now yielding to the efforts of Artios and others, as novel first-in-class agents approach the clinic.\u00a0<\/span><\/p>\n

As we now move toward therapeutics to interfere with transcription factors, RNA processing and other targets, alongside the active stabilisation of tumour suppressors such as p53, perhaps it is now finally time to retire the term \u201cundruggable\u201d?\u00a0 More and more, it seems, \u201cit\u2019s only undruggable until we learn how to do it\u2026\u201d\u00a0<\/span><\/p>\n

\u00a0<\/p>\n

Progress with <\/span>PROTACs<\/span> is exciting but challenges remain<\/span><\/span>\u00a0<\/span><\/strong><\/h2>\n

Continuing this theme of how to drug the undruggable was the increased interest in new modalities that target proteins for degradation, in particular PROTACs and molecular glues. This \u201crecent\u201d modality showed great promise as demonstrated by the advance of several compounds of known targets to clinical trials.\u00a0<\/span><\/p>\n

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There are several advantages compared to the more \u201ctraditional\u201d small molecules. Their potential ability to target the so-called undruggable proteome, alongside the fact that they do not need functional binding, should open the door to multiple new targets and\/or hard-to-drug targets. Their catalytic mode of action might also give the opportunity of lower dosing and should, in theory, reduce the risk of side-effects and toxicity. Another possible great benefit of degraders comes from the choice of the E3 ligase, as some are restricted to particular tissues.\u00a0<\/span><\/p>\n

These efforts have significantly expanded the number of tractable drug targets as, at least in theory (although its rarely that simple!), a ligand that binds anywhere on the target protein can be used to recruit the protein degradation machinery. The PROTAC approach, using bifunctional molecules, was well represented with new disclosures on targets including Brd9 and Aurora-A.\u00a0<\/span><\/p>\n

Despite exciting progress with PROTACs<\/a>, there are still some challenges that need to be overcome:\u00a0<\/span><\/p>\n