Lorlatinib (PF-06463922) is under clinical development as an inhibitor for both wild type ALK and Xalkori resistant ALK mutants.   Because brain metastates has been seen in patients with NSCLC, PF-06463922 was also designed to be brain penetrant. Given the potential for numerous adverse effects due to off-target activity, kinase selectivity was prioritized as a key goal within the discovery cascade for this program. With both this, and a desire to reduce synthetic complexity, a series of macrocycles were accessed featuring removal of the one chiral element present in the lead series. Although, high levels of desired selectivity were observed, the compounds also were observed to be atropisomers. The talk will focus on our studies of this phenomenon in our lead series, and further efforts to mitigate this whilst maintaining the potency required to deliver a development candidate.  <br/>

Optimizing kinase in the development of lorlatinib: The challenge of atropisomerism

255th National Meeting (2018)

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