Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

Abstract

Members of the BET family of bromodomain containing proteins have been identified as potential targets for blocking proliferation in a variety of cancer cell lines. A two-dimensional NMR fragment screen for binders to the bromodomains of BRD4 identified a phenylpyridazinone fragment with a weak binding affinity (1, K = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of potent pyridone and macrocyclic pyridone inhibitors exhibiting single digit nanomolar potency in both biochemical and cell based assays. Advanced analogs in these series exhibited high oral exposures in rodent PK studies and demonstrated significant tumor growth inhibition efficacy in mouse flank xenograft models.

Drug Discovery Targeting Bromodomain-Containing Protein 4

“…Compounds 57 and 58 (Figure 15), developed by AbbVie, display both potent BRD4 BD1 and BD2 inhibitory activity (up to single-digit nanomolar) in vitro, but their cellular activities are not very consistent (submicromolar range). 139 Compounds 59 and 60 , 140 fused with a 12-membered ring, exhibit dramatically improved antiproliferative activity in cellular assays (MX-1 cell lines) with EC 50 values of 5.7 and 8.7 nM, respectively. Their ability to inhibit LPS-induced IL-6 production was confirmed (83 and 81%, respectively) in a mouse model.…”

“…Compounds 65 – 67 exhibit similar BRD4 BD1 and BD2 inhibitory activities with IC 50 values at the single-digit nanomolar level. 143 Compared to compound 6 , which is in Phase III clinical trials, an additional morpholine was introduced to give compound 68 , and its potency indicated that the 5-position of the phenyl ring is tolerable. 143 A long side chain was introduced to pyrrole of compounds 69 and 70 , which both showed potent BRD4 inhibitory activities with IC 50 values in the single-digit nanomolar range.…”

“…143 Compared to compound 6 , which is in Phase III clinical trials, an additional morpholine was introduced to give compound 68 , and its potency indicated that the 5-position of the phenyl ring is tolerable. 143 A long side chain was introduced to pyrrole of compounds 69 and 70 , which both showed potent BRD4 inhibitory activities with IC 50 values in the single-digit nanomolar range. 143 They inhibited cell proliferation with EC 50 values of 9.4 and 48 nM, respectively, against the MX-1 cell line.…”

“…143 A long side chain was introduced to pyrrole of compounds 69 and 70 , which both showed potent BRD4 inhibitory activities with IC 50 values in the single-digit nanomolar range. 143 They inhibited cell proliferation with EC 50 values of 9.4 and 48 nM, respectively, against the MX-1 cell line.…”

Bromodomain as New Targets in Drug Discovery

“…Despite that, selective BRD4 inhibitors have been reported in the literature. Researchers have described thienopyridinone, furopyridine and tetrahydroquinoline compounds 10-fold more selective for BRD4(1) than BRD4(2) [14]. On the other hand, compounds such as RVX-208 was 40-fold selective for BRD4(2) than BRD4(1) [15].…”